TY - JOUR A1 - Schmid, Michael A1 - Evans, Ben J. A1 - Bogart, James P. T1 - Polyploidy in Amphibia JF - Cytogenetic and Genome Research N2 - This review summarizes the current status of the known extant genuine polyploid anuran and urodelan species, as well as spontaneously originated and/or experimentally produced amphibian polyploids. The mechanisms by which polyploids can originate, the meiotic pairing configurations, the diploidization processes operating in polyploid genomes, the phenomenon of hybridogenesis, and the relationship between polyploidization and sex chromosome evolution are discussed. The polyploid systems in some important amphibian taxa are described in more detail. KW - allopolyploidy KW - Anura KW - autopolyploidy KW - diploidization KW - hybridogenesis KW - polyploidization KW - sex chromosome evolution KW - Urodela Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196730 SN - 1424-8581 SN - 1424-859X N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 145 IS - 3-4 ER - TY - JOUR A1 - Matthes, Philipp R. A1 - Schönfeld, Fabian A1 - Zottnick, Sven H. A1 - Müller-Buschbaum, Klaus T1 - Post-synthetic shaping of porosity and crystal structure of Ln-Bipy-MOFs by thermal treatment JF - Molecules N2 - The reaction of anhydrous lanthanide chlorides together with 4,4'-bipyridine yields the MOFs \(^{2}\)\(_{∞}\)[Ln\(_{2}\)Cl\(_{6}\)(bipy)\(_{3}\)]*2bipy, with Ln = Pr-Yb, bipy = 4,4'-bipyridine, and \(^{3}\)\(_{∞}\)[La\(_{2}\)Cl\(_{6}\)(bipy)\(_{5}\)]*4bipy. Post-synthetic thermal treatment in combination with different vacuum conditions was successfully used to shape the porosity of the MOFs. In addition to the MOFs microporosity, a tuneable mesoporosity can be implemented depending on the treatment conditions as a surface morphological modification. Furthermore, thermal treatment without vacuum results in several identifiable crystalline high-temperature phases. Instead of collapse of the frameworks upon heating, further aggregation under release of bipy is observed. \(^{3}\)\(_{∞}\)[LaCl\(_{3}\)(bipy)] and \(^{2}\)\(_{∞}\)[Ln\(_{3}\)Cl\(_{9}\)(bipy)\(_{3}\)], with Ln = La, Pr, Sm, and \(^{1}\)\(_{∞}\)[Ho\(_{2}\)Cl\(_{6}\)(bipy)\(_{2}\)] were identified and characterized, which can also exhibit luminescence. Besides being released upon heating, the linker 4,4'-bipyridine can undergo activation of C-C bonding in ortho-position leading to the in-situ formation of 4,4':2',2 '':4 '',4'''-quaterpyridine (qtpy). qtpy can thereby function as linker itself, as shown for the formation of the network \(^{2}\)\(_{∞}\)[Gd\(_{2}\)Cl\(_{6}\)(qtpy)\(_{2}\)(bipy)\(_{2}\)]*bipy. Altogether, the manuscript elaborates the influence of thermal treatment beyond the usual activation procedures reported for MOFs. KW - energy transfer KW - ligand KW - Ln-MOFs KW - luminescence crystal structure KW - metal-organic frameworks KW - shaping of porosity KW - thermal treatment KW - luminescence KW - crystal scructure KW - coordination polymers KW - solid state Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148404 VL - 20 ER - TY - JOUR A1 - Varagnolo, Linda A1 - Lin, Quiong A1 - Obier, Nadine A1 - Plass, Christoph A1 - Dietl, Johannes A1 - Zenke, Martin A1 - Claus, Rainer A1 - Müller, Albrecht M. T1 - PRC2 inhibition counteracts the culture-associated loss of engraftment potential of human cord blood-derived hematopoietic stem and progenitor cells JF - Scientific Reports N2 - Cord blood hematopoietic stem cells (CB-HSCs) are an outstanding source for transplantation approaches. However, the amount of cells per donor is limited and culture expansion of CB-HSCs is accompanied by a loss of engraftment potential. In order to analyze the molecular mechanisms leading to this impaired potential we profiled global and local epigenotypes during the expansion of human CB hematopoietic stem and progenitor cells (HPSCs). Human CB-derived CD34+ cells were cultured in serum-free medium together with SCF, TPO, FGF, with or without Igfbp2 and Angptl5 (STF/STFIA cocktails). As compared to the STF cocktail, the STFIA cocktail maintains in vivo repopulation capacity of cultured CD34+ cells. Upon expansion, CD34+ cells genome-wide remodel their epigenotype and depending on the cytokine cocktail, cells show different HK4me3 and H3K27me3 levels. Expanding cells without Igfbp2 and Angptl5 leads to higher global H3K27me3 levels. ChIPseq analyses reveal a cytokine cocktail-dependent redistribution of H3K27me3 profiles. Inhibition of the PRC2 component EZH2 counteracts the culture-associated loss of NOD scid gamma (NSG) engraftment potential. Collectively, our data reveal chromatin dynamics that underlie the culture-associated loss of engraftment potential. We identify PRC2 component EZH2 as being involved in the loss of engraftment potential during the in vitro expansion of HPSCs. KW - ex vivo expansion KW - epigenomic landscapes KW - in vivo polycomb KW - transplantation states genes KW - EZH2 differentiation trichostatin Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148374 VL - 5 IS - 12319 ER - TY - JOUR A1 - Køllgaard, Tania A1 - Ugurel-Becker, Selma A1 - Idorn, Manja A1 - Andersen, Mads Hald A1 - Becker, Jürgen C. A1 - Straten, Per thor T1 - Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes JF - PLoS One N2 - Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses as well as clinical outcome in metastatic melanoma patients vaccinated with survivin-derived peptides. Notably, we observed dysfunctional Th1 and cytotoxic T cells, i.e. down-regulation of the CD3\(\zeta\)chain (p=0.001) and an impaired IFN\(\gamma\)-production (p=0.001) in patients compared to healthy donors, suggesting an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4\(^{+}\) T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high frequencies of Th17 cells at pre-vaccination were more likely to develop survivin-specific T-cell reactivity post-vaccination (p=0.03). Furthermore, the frequency of Th17 (p=0.09) and Th17/IFN\(\gamma\)\(^{+}\) (p=0.19) cells associated with patient survival after vaccination. In summary, our explorative, hypothesis-generating study demonstrated that immune regulatory cells, in particular Th17 cells, play a relevant role for generation of the vaccine-induced anti-tumor immunity in cancer patients, hence warranting further investigation to test for validity as predictive biomarkers. KW - suppressor cells KW - melanoma patients KW - patient survival KW - cancer patients KW - Th17 KW - tumor immunity KW - blood Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151509 VL - 10 IS - 7 ER - TY - JOUR A1 - Adelfinger, Marion A1 - Bessler, Simon A1 - Cecil, Alexander A1 - Langbein-Laugwitz, Johanna A1 - Frentzen, Alexa A1 - Gentschev, Ivaylo A1 - Szalay, Aladar A. T1 - Preclinical Testing Oncolytic Vaccinia Virus Strain GLV-5b451 Expressing an Anti-VEGF Single-Chain Antibody for Canine Cancer Therapy JF - Viruses N2 - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a novel approach for canine cancer therapy. Here we describe, for the first time, the characterization and the use of VACV strain GLV-5b451 expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as therapeutic agent against different canine cancers. Cell culture data demonstrated that GLV-5b451 efficiently infected and destroyed all four tested canine cancer cell lines including: mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258), and soft tissue sarcoma (STSA-1). The GLV-5b451 virus-mediated production of GLAF-2 antibody was observed in all four cancer cell lines. In addition, this antibody specifically recognized canine VEGF. Finally, in canine soft tissue sarcoma (CSTS) xenografted mice, a single systemic administration of GLV-5b451 was found to be safe and led to anti-tumor effects resulting in the significant reduction and substantial long-term inhibition of tumor growth. A CD31-based immuno-staining showed significantly decreased neo-angiogenesis in GLV-5b451-treated tumors compared to the controls. In summary, these findings indicate that GLV-5b451 has potential for use as a therapeutic agent in the treatment of CSTS. KW - canine cancer therapy KW - canine soft tissue sarcoma (CSTS) KW - oncolytic virus KW - cancer KW - canine cancer cell lines KW - antibody production KW - angiogenesis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125705 VL - 7 ER - TY - THES A1 - Stehr, Vera T1 - Prediction of charge and energy transport in organic crystals with quantum chemical protocols employing the hopping model T1 - Vorhersage des Ladungs- und Energietransports in organischen Kristallen mit quantenchemischen Methoden unter Verwendung des Sprungmodells N2 - As organic semiconductors gain more importance for application, research into their properties has become necessary. This work investigated the exciton and charge transport properties of organic semiconducting crystals. Based on a hopping approach, protocols have been developed for the calculation of Charge mobilities and singlet exciton diffusion coefficients. The protocols do not require any input from experimental data except for the x-ray crystal structure, since all needed quantities can be taken from high-level quantum chemical calculations. Hence, they allow to predict the transport properties of yet unknown compounds for given packings, which is important for a rational design of new materials. Different thermally activated hopping models based on time-dependent perturbation theory were studied for the charge and exciton transport; i. e. the spectral overlap approach, the Marcus theory, and the Levich-Jortner theory. Their derivations were presented coherently in order to emphasize the different levels of approximations and their respective prerequisites. A short reference was made to the empirical Miller-Abrahams hopping rate. Rate equation approaches to calculate the stationary charge carrier mobilities and exciton diffusion coefficients have been developed, which are based on the master equation. The rate equation approach is faster and more efficient than the frequently used Monte Carlo method and, therefore, provides the possibility to study the anisotropy of the transport parameters and their three-dimensional representation in the crystal. The Marcus theory, originally derived for outer sphere electron transfer in solvents, had already been well established for charge transport in organic solids. It was shown that this theory fits even better for excitons than for charges compared with the experiment. The Levich-Jortner theory strongly overestimates the charge carrier mobilities and the results deviate even stronger from the experiment than those obtained with the Marcus theory. The latter contains larger approximations by treating all vibrational modes classically. The spectral overlap approach in combination with the developed rate equations leads to even quantitatively very good results for exciton diffusion lengths compared to experiment. This approach and the appendant rate equations have also been adapted to charge transport. The Einstein relation, which relates the diffusion coefficient with the mobility, is important for the rate equations, which have been developed here for transport in organic crystals. It has been argued that this relation does not hold in disordered organic materials. This was analyzed within the Framework of the Gaussian disorder model and the Miller-Abrahams hopping rate. N2 - Organische Halbleiter gewinnen immer größere Bedeutung für Anwendungen in der Elektronik. In dieser Arbeit wurden deren Eigenschaften bezüglich des Exzitonen- und Ladungstransports untersucht. Diese beiden Prozesse sind wesentlich für viele Bauteile der organischen Elektronik, wie zum Beispiel Solarzellen. Ausgehend von einem Sprungmodell wurden Verfahren zur Berechnung von Ladungsträgerbeweglichkeiten und Diffusionskoeffizienten von Singulettanregungen entwickelt, wofür bis auf die Röntgenstruktur des Kristalls keine weiteren experimentellen Daten benötigt werden, da alle notwendigen Größen durch quantenchemische Rechnungen auf hohem Niveau bestimmt werden können. Dies ermöglicht die Vorhersage der Transporteigenschaften von noch unbekannten Materialien mit bekannter Struktur, was eine Voraussetzung für das Maßschneidern neuer Materialien darstellt. Verschiedene, auf der zeitabhängigen Störungstheorie basierende thermisch aktivierte Sprungmodelle - der spektrale Überlappungsansatz, die Marcus- und die Levich-Jortner-Theorie - wurden für die Anwendung auf den Ladungs- und Energietransport hin untersucht. Ausgehend von Fermis Goldener Regel wurden die Sprunggleichungen konsistent hergeleitet, um die verschiedenen Abstufungen der jeweils vorgenommenen Näherungen und deren Voraussetzungen deutlich zu machen. Zusätzlich dazu wurde ein kurzer Exkurs zur empirischen Miller-Abrahams-Sprungrate und deren Anwendung in amorphen Systemen gemacht. Unter Verwendung der Mastergleichung wurden Ratengleichungsansätze zur Berechnung der stationären Ladungsträgerbeweglichkeiten und Exzitonendiffusionskoeffizienten entwickelt. Die Berechnung der Transportgrößen über Ratengleichungen ist wesentlich schneller und effizienter als die häufig angewendete Monte-Carlo-Simulation. Dies ermöglicht die Analyse der Anisotropie des Transports im Kristall und ihre dreidimensionale Darstellung. Die Marcustheorie, die ursprünglich für Elektronentransfer in Lösungen entwickelt wurde, hat sich auch für Ladungstransport in organischen Festkörpern bewährt. Hier wurde diese Theorie auch auf Exzitonentransport übertragen und gezeigt, daß sie im Vergleich zum Experiment für Exzitonen sogar bessere Ergebnisse liefert als für Ladungsträger. Die Levich-Jortner-Theorie überschätzt die Ladungsträgerbeweglichkeiten im Falle der Acene sehr stark. Ihre Ergebnisse weichen sogar stärker vom Experiment ab als die der Marcustheorie. Letztere enthält deutlich stärkere Näherungen, weil alle Molekülschwingungen klassisch behandelt werden. Der spektrale Überlappungsansatz führt zusammen mit den hier entwickelten Ratengleichungen sogar zu quantitativ guten Ergebnissen für die Exzitonendiffusion. Dieser Ansatz und die Ratengleichungen wurden auch für die Berechnung der Ladungsträgerbeweglichkeiten angepaßt. Für die in dieser Arbeit entwickelten Ratengleichungen ist die Einsteinrelation, welche die Diffusion mit der Drift in Beziehung setzt, von zentraler Bedeutung. Es ist umstritten, ob diese Beziehung auch in amorphen, ungeordneten Materialien gültig ist. Dieser Frage wurde im Rahmen des Gaußschen Unordnungsmodells und der Miller-Abrahams-Sprungrate nachgegangen. KW - Exziton KW - exciton KW - Ladungstransfer KW - charge transfer KW - organische Halbleiter KW - organic semiconductors KW - Sprungmodell KW - hopping model Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114940 ER - TY - JOUR A1 - Gulberti, A. A1 - Moll, C.K.E. A1 - Hamel, W. A1 - Buhmann, C. A1 - Koeppen, J.A. A1 - Boelmans, K. A1 - Zittel, S. A1 - Gerloff, C. A1 - Westphal, M. A1 - Schneider, T.R. A1 - Engel, A.K. T1 - Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus Impaired beta-band timing functions in PD JF - NeuroImage: Clinical N2 - Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing. KW - Parkinson's disease KW - interval timing KW - beta oscillations KW - subthalamic nucleus KW - deep brain stimulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150049 VL - 9 ER - TY - JOUR A1 - Mueller, A. A1 - Stoetter, L. A1 - Kalluvya, S. A1 - Stich, A. A1 - Majinge, C. A1 - Weissbrich, B. A1 - Kasang, C. T1 - Prevalence of hepatitis B virus infection among health care workers in a tertiary hospital in Tanzania JF - BMC Infectious Diseases N2 - Background: Sub-Saharan Africa has a high prevalence of hepatitis B virus (HBV) infections. Health care workers (HCWs) are at high risk of contracting HBV infection through their occupation. Vaccination of HCWs against HBV is standard practice in many countries, but is often not implemented in resource-poor settings. We aimed with this cross-sectional study to determine HBV prevalence, HCW vaccination status, and the risk factors for HCWs contracting HBV infection in Tanzania. Methods: We enrolled 600 HCWs from a tertiary Tanzanian hospital. Their demographics, medical histories, HBV vaccination details and risk factors for contracting blood-borne infections were collected using a standardized questionnaire. Serum samples were tested for HBV and hepatitis C virus (HCV) markers by ELISA techniques, PCR and an anti-HBs rapid test. HCWs were divided in two subgroups: those at risk of contracting HBV (rHCW 79.2 %) via exposure to potentially infectious materials, and those considered not at risk of contracting HBV (nrHCW, 20.8 %). Results: The overall prevalence of chronic HBV infection (HBsAg+, anti-HBc+, anti-HBs-) was 7.0 % (42/598). Chronic HBV infection was found in 7.4 % of rHCW versus 5.6 % of nrHCW(p-value = 0.484). HCWs susceptible to HBV (HBsAg-, anti-HBc-, anti-HBs-) comprised 31.3 %. HBV immunity achieved either by healed HBV infection (HBsAg-, anti-HBc+, anti-HBs+) or by vaccination (HBsAg-, anti-HBc-, anti-HBs+) comprised 36.5 % and 20.2 %, respectively. 4.8 % of participants had indeterminate results (HBsAg-, anti-HBc+, anti-HBc-IgM-, anti-HBs-). Only 77.1 % of HCWs who received a full vaccination course had an anti-HBs titer > 10 ml/U. An anti-HBs point-of-care test was 80.7 % sensitive and 96.9 % specific. There was a significantly higher risk for contracting HBV (anti-HBc+) among those HCW at occupational risk (rHCW) of older age (odds ratios (OR) in rHCW 3.297, p < 0.0001 vs. nrHCW 1.385, p = 0.606) and among those HCW being employed more than 11 years (OR 2.51, p < 0.0001***). HCV prevalence was low (HCV antibodies 1.2 % and HCV-RNA 0.3 %). Conclusions: Chronic HBV infection is common among Tanzanian HCWs. One third of HCWs were susceptible to HBV infection, highlighting the need for vaccination. Due to high prevalence of naturally acquired immunity against HBV pre-testing might be a useful tool to identify susceptible individuals. KW - hepatitis C virus KW - point-of-care test KW - human-immunodeficiency-virus KW - C virus KW - seroprevalence KW - syphilis KW - vaccine KW - Uganda KW - blood KW - hepatitis B virus KW - health care workers KW - Tanzania Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141786 VL - 15 IS - 386 ER - TY - JOUR A1 - Zhao, De-Wei A1 - Yu, Mang A1 - Hu, Kai A1 - Wang, Wei A1 - Yang, Lei A1 - Wang, Ben-Jie A1 - Gao, Xiao-Hong A1 - Guo, Yong-Ming A1 - Xu, Yong-Qing A1 - Wei, Yu-Shan A1 - Tian, Si-Miao A1 - Yang, Fan A1 - Wang, Nan A1 - Huang, Shi-Bo A1 - Xie, Hui A1 - Wei, Xiao-Wei A1 - Jiang, Hai-Shen A1 - Zang, Yu-Qiang A1 - Ai, Jun A1 - Chen, Yuan-Liang A1 - Lei, Guang-Hua A1 - Li, Yu-Jin A1 - Tian, Geng A1 - Li, Zong-Sheng A1 - Cao, Yong A1 - Ma, Li T1 - Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey JF - Chinese Medical Journal N2 - Background: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating disease that represents a significant financial burden for both individuals and healthcare systems. Despite its significance, however, its prevalence in the Chinese general population remains unknown. This study aimed to investigate the prevalence of NONFH and its associated risk factors in the Chinese population. Methods: A nationally representative survey of 30,030 respondents was undertaken from June 2012 to August 2013. All participants underwent a questionnaire investigation, physical examination of hip, and bilateral hip joint X-ray and/or magnetic resonance imaging examination. Blood samples were taken after overnight fasting to test serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels. We then used multivariate logistic regression analysis to investigate the associations between various metabolic, demographic, and lifestyle-related variables and NONFH. Results: NONFH was diagnosed in 218 subjects (0.725%) and the estimated NONFH cases were 8.12 million among Chinese people aged 15 years and over. The prevalence of NONFH was significantly higher in males than in females (1.02% vs. 0.51%, \(\chi^2\) = 24.997, P < 0.001). Among NONFH patients, North residents were subjected to higher prevalence of NONFH than that of South residents (0.85% vs. 0.61%, \(\chi^2\) = 5.847, P = 0.016). Our multivariate regression analysis showed that high blood levels of triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, male, urban residence, family history of osteonecrosis of the femoral head, heavy smoking, alcohol abuse and glucocorticoid intake, overweight, and obesity were all significantly associated with an increased risk of NONFH. Conclusions: Our findings highlight that NONFH is a significant public health challenge in China and underscore the need for policy measures on the national level. Furthermore, NONFH shares a number of risk factors with atherosclerosis. KW - nontraumatic osteonecrosis of the femoral head KW - risk factors KW - idiopathic osteonecrosis KW - early-stage osteonecrosis KW - implantation KW - bone KW - marrow KW - follow-up KW - intake KW - avascular necrosis KW - occupational-status KW - cigarette smoking KW - alcohol KW - prevalence Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138482 VL - 128 IS - 21 ER - TY - THES A1 - Navarro Bullock, Beate T1 - Privacy aware social information retrieval and spam filtering using folksonomies T1 - Suche und Spam Entdeckung anhand von Folksonomien unter Beachtung datenschutzrelevanter Aspekte N2 - Social interactions as introduced by Web 2.0 applications during the last decade have changed the way the Internet is used. Today, it is part of our daily lives to maintain contacts through social networks, to comment on the latest developments in microblogging services or to save and share information snippets such as photos or bookmarks online. Social bookmarking systems are part of this development. Users can share links to interesting web pages by publishing bookmarks and providing descriptive keywords for them. The structure which evolves from the collection of annotated bookmarks is called a folksonomy. The sharing of interesting and relevant posts enables new ways of retrieving information from the Web. Users can search or browse the folksonomy looking at resources related to specific tags or users. Ranking methods known from search engines have been adjusted to facilitate retrieval in social bookmarking systems. Hence, social bookmarking systems have become an alternative or addendum to search engines. In order to better understand the commonalities and differences of social bookmarking systems and search engines, this thesis compares several aspects of the two systems' structure, usage behaviour and content. This includes the use of tags and query terms, the composition of the document collections and the rankings of bookmarks and search engine URLs. Searchers (recorded via session ids), their search terms and the clicked on URLs can be extracted from a search engine query logfile. They form similar links as can be found in folksonomies where a user annotates a resource with tags. We use this analogy to build a tripartite hypergraph from query logfiles (a logsonomy), and compare structural and semantic properties of log- and folksonomies. Overall, we have found similar behavioural, structural and semantic characteristics in both systems. Driven by this insight, we investigate, if folksonomy data can be of use in web information retrieval in a similar way to query log data: we construct training data from query logs and a folksonomy to build models for a learning-to-rank algorithm. First experiments show a positive correlation of ranking results generated from the ranking models of both systems. The research is based on various data collections from the social bookmarking systems BibSonomy and Delicious, Microsoft's search engine MSN (now Bing) and Google data. To maintain social bookmarking systems as a good source for information retrieval, providers need to fight spam. This thesis introduces and analyses different features derived from the specific characteristics of social bookmarking systems to be used in spam detection classification algorithms. Best results can be derived from a combination of profile, activity, semantic and location-based features. Based on the experiments, a spam detection framework which identifies and eliminates spam activities for the social bookmarking system BibSonomy has been developed. The storing and publication of user-related bookmarks and profile information raises questions about user data privacy. What kinds of personal information is collected and how do systems handle user-related items? In order to answer these questions, the thesis looks into the handling of data privacy in the social bookmarking system BibSonomy. Legal guidelines about how to deal with the private data collected and processed in social bookmarking systems are also presented. Experiments will show that the consideration of user data privacy in the process of feature design can be a first step towards strengthening data privacy. N2 - Soziale Interaktion, wie sie im letzten Jahrzehnt durch Web 2.0 Anwendungen eingeführt wurde, änderte die Art und Weise wie wir das Internet nutzen. Heute gehört es zum Alltag, Kontakte in sozialen Netzwerken zu pflegen, die aktuellsten Entwicklungen in Mikroblogging - Anwendungen zu kommentieren, oder interessante Informationen wie Fotos oder Weblinks digital zu speichern und zu teilen. Soziale Lesezeichensysteme sind ein Teil dieser Entwicklung. Nutzer können Links zu interessanten Webseiten teilen, indem sie diese mit aussagekräftigen Begriffen (Tags) versehen und veröffentlichen. Die Struktur, die aus der Sammlung von annotierten Lesezeichen entsteht, wird Folksonomy genannt. Nutzer können diese durchforsten und nach Links mit bestimmten Tags oder von bestimmten Nutzern suchen. Ranking Methoden, die schon in Suchmaschinen implementiert wurden, wurden angepasst, um die Suche in sozialen Lesezeichensystemen zu erleichtern. So haben sich diese Systeme mittlerweile zu einer ernsthaften Alternative oder Ergänzung zu traditionellen Suchmaschinen entwickelt. Um Gemeinsamkeiten und Unterschiede in der Struktur, Nutzung und in den Inhalten von sozialen Lesezeichensystemen und Suchmaschinen besser zu verstehen, werden in dieser Arbeit die Verwendung von Tags und Suchbegriffen, die Zusammensetzung der Dokumentensammlungen und der Aufbau der Rankings verglichen und diskutiert. Aus den Suchmaschinennutzern eines Logfiles, ihren Anfragen und den geklickten Rankingergebnissen lässt sich eine ähnlich tripartite Struktur wie die der Folksonomy aufbauen. Die Häufigkeitsverteilungen sowie strukturellen Eigenschaften dieses Graphen werden mit der Struktur einer Folksonomy verglichen. Insgesamt lassen sich ein ähnliches Nutzerverhalten und ähnliche Strukturen aus beiden Ansätzen ableiten. Diese Erkenntnis nutzend werden im letzten Schritt der Untersuchung Trainings- und Testdaten aus Suchmaschinenlogfiles und Folksonomien generiert und ein Rankingalgorithmus trainiert. Erste Analysen ergeben, dass die Rankings generiert aus impliziten Feedback von Suchmaschinen und Folksonomien, positiv korreliert sind. Die Untersuchungen basieren auf verschiedenen Datensammlungen aus den sozialen Lesezeichensystemen BibSonomy und Delicious, und aus Daten der Suchmaschinen MSN (jetzt Bing) und Google. Damit soziale Lesezeichensysteme als qualitativ hochwertige Informationssysteme erhalten bleiben, müssen Anbieter den in den Systemen anfallenden Spam bekämpfen. In dieser Arbeit werden verschiedene Merkmale vom legitimen und nicht legitimen Nutzern aus den Besonderheiten von Folksonomien abgeleitet und auf ihre Eignung zur Spamentdeckung getestet. Die besten Ergebnisse ergeben eine Kombination aus Profil- Aktivitäts-, semantischen und ortsbezogenen Merkmalen. Basierend auf den Experimenten wird eine Spamentdeckungsanwendung entwickelt mit Hilfe derer Spam in sozialen Lesezeichensystem BibSonomy erkannt und eliminiert wird. Mit der Speicherung und Veröffentlichung von benutzerbezogenen Daten ergibt sich die Frage, ob die persönlichen Daten eines Nutzers in sozialen Lesezeichensystemen noch genügend geschützt werden. Welche Art der persönlichen Daten werden in diesen Systemen gesammelt und wie gehen existierende Systeme mit diesen Daten um? Um diese Fragen zu beantworten, wird die Anwendung BibSonomy unter technischen und datenschutzrechtlichen Gesichtspunkten analysiert. Es werden Richtlinien erarbeitet, die als Leitfaden für den Umgang mit persönlichen Daten bei der Entwicklung und dem Betrieb von sozialen Lesezeichen dienen sollen. Experimente zur Spamklassifikation zeigen, dass die Berücksichtigung von datenschutzrechtlichen Aspekten bei der Auswahl von Klassifikationsmerkmalen persönliche Daten schützen können, ohne die Performanz des Systems bedeutend zu verringern. KW - Information Retrieval KW - Data Mining KW - Web2.0 KW - Tagging KW - Spam Detection KW - Soziales Netzwerk Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120941 ER - TY - JOUR A1 - Kleint, Nina I. A1 - Wittchen, Hans-Ulrich A1 - Lueken, Ulrike T1 - Probing the interoceptive network by listening to heartbeats: an fMRI study JF - PLoS ONE N2 - Exposure to cues of homeostatic relevance (i.e. heartbeats) is supposed to increase the allocation of attentional resources towards the cue, due to its importance for self-regulatory, interoceptive processes. This functional magnetic resonance imaging (fMRI) study aimed at determining whether listening to heartbeats is accompanied by activation in brain areas associated with interoception, particularly the insular cortex. Brain activity was measured with fMRI during cue-exposure in 36 subjects while listening to heartbeats vs. sinus tones. Autonomic markers (skin conductance) and subjective measures of state and trait anxiety were assessed. Stimulation with heartbeat sounds triggered activation in brain areas commonly associated with the processing of interoceptive information, including bilateral insular cortices, the inferior frontal operculum, and the middle frontal gyrus. A psychophysiological interaction analysis indicated a functional connectivity between the middle frontal gyrus (seed region) and bilateral insular cortices, the left amygdala and the supplementary motor area. The magnitude of neural activation in the right anterior insular cortex was positively associated with autonomic arousal. The present findings indicate that listening to heartbeats induced activity in areas of the interoception network as well as changes in psychophysiological arousal and subjective emotional experience. As this approach constitutes a promising method for studying interoception in the fMRI environment, a clinical application in anxiety prone populations should be addressed by future studies. KW - inferior parietal lobule KW - brain activation KW - cortex KW - awareness KW - perception KW - cardiovascular arousal KW - panic disorder KW - humans KW - anterior insula KW - emotional experience Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148330 VL - 10 IS - 7 ER - TY - RPRT A1 - Winkelmann, Axel ED - Winkelmann, Axel T1 - Proceedings of the Doctoral Consortium WI 2015 T1 - Tagungsband zum Doctoral Consortium der WI 2015 N2 - Bereits seit Anfang der 1990er Jahre wird jungen Wissenschaftlern im Vorfeld der Tagung "Wirtschaftsinformatik" ein Doctoral Consortium als unterstützendes Forum angeboten. Diese Einrichtung wurde auch zur größten Internationalen Konferenz der Wirtschaftsinformatik, der WI 2015 in Osnabrück fortgeführt. Dieser Band fasst die zum Vortag ausgewählten Beiträge zusammen. T3 - Working Paper Series of the Institute of Business Management - 4 KW - Wirtschaftsinformatik KW - Doctorial Consortium, WI 2015 KW - Tagung KW - 2015 KW - Osnabrück Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111715 SN - 2199-0328 ER - TY - JOUR A1 - Werner, R.A. A1 - Schmid, J.S. A1 - Muegge, D.O. A1 - Lückerath, K. A1 - Higuchi, T. A1 - Hänscheid, H. A1 - Grelle, I. A1 - Reiners, C. A1 - Herrmann, K. A1 - Buck, A.K. A1 - Lapa, C. T1 - Prognostic value of serum tumor markers in medullary thyroid cancer patients undergoing vandetanib treatment JF - Medicine N2 - Tyrosine kinase inhibitors (TKIs) such as vandetanib have shown clinical effectiveness in advanced medullary thyroid cancer (MTC). During TKI treatment, fluctuations in the tumor markers carcinoembryonic antigen (CEA) and calcitonin (CTN) are frequently observed. Their role for treatment monitoring and the decision-making process has not been fully elucidated yet. Twenty-one patients (male, 16, female, 5; mean age, 49±13 years) with progressive MTC receiving vandetanib (300mg orally per day) were considered. Tumor restaging was performed every 3 months including contrast-enhanced computed tomography (CT). Response was assessed according to recent criteria (Response Evaluation Criteria in Solid Tumors, RECIST 1.1). Additionally, CEA and CTN were measured at the day of CT imaging and alterations observed in tumor markers were compared to respective imaging findings (partial response, PR; stable disease, SD; progressive disease, PD). During long-term follow-up (510±350 days [range, 97-1140 days]), CTN and CEA levels initially dropped in 71.4% and 61.9% of the patients followed by fluctuations in serum marker levels. A rise in CTN ≥39.5% between 2 subsequent measurements (defined by ROC analysis) had a sensitivity of 70.6% and a specificity of 83.2% in predicting PD with an accuracy of 82.0% (area under the curve (AUC), 0.76). Oscillations in CEA levels were not predictive for PD. Whereas tumor marker fluctuations in MTC patients undergoing TKI treatment are a frequent phenomenon, a significant rise in CTN ≥40% turns out to as an early indicator of tumor progression. KW - follow-up KW - kinase inhibitor KW - carcinoma KW - calcitonin KW - trial KW - medullary thyroid cancer Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145154 VL - 94 IS - 45 ER - TY - JOUR A1 - Lang, Stefan J. A1 - Messmer, Elisabeth M. A1 - Geerling, Gerd A1 - Mackert, Marc J. A1 - Brunner, Tobias A1 - Dollak, Sylvia A1 - Kutchoukov, Borislav A1 - Böhringer, Daniel A1 - Reinhard, Thomas A1 - Maier, Philip T1 - Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus JF - BMC Ophthalmology N2 - Background: Corneal cross-linking is widely used to treat keratoconus. However, to date, only limited data from randomized trials support its efficacy. Methods: The efficacy and safety of corneal cross-linking for halting progression of keratoconus were investigated in a prospective, randomized, blinded, placebo controlled, multicentre trial. Twenty-nine keratoconus patients were randomized in three trial centres. The mean age at inclusion was 28 years. Longitudinal changes in corneal refraction were assessed by linear regression. The best corrected visual acuity, surface defects and corneal inflammation were also assessed. These data were analysed with a multifactorial linear regression model. Results: A total of 15 eyes were randomized to the treatment and 14 to the control group. Follow-up averaged 1098 days. Corneal refractive power decreased on average (+/-standard deviation) by 0.35 +/- 0.58 dioptres/year in the treatment group. The controls showed an increase of 0.11 +/- 0.61 dioptres/year. This difference was statistically significant (p = 0.02). Conclusions: Our data suggest that corneal cross-linking is an effective treatment for some patients to halt the progression of keratoconus. However, some of the treated patients still progressed, whereas some untreated controls improved. Therefore, further investigations are necessary to decide which patients require treatment and which do not. KW - ultraviolet-a KW - riboflavin KW - Scheimpflug KW - eyes KW - haze Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151498 VL - 15 IS - 78 ER - TY - THES A1 - Schubert, Andreas T1 - Protein kinases as targets for the development of novel drugs against alveolar echinococcosis T1 - Proteinkinasen als Angriffspunkte für die Entwicklung neuer Chemotherapeutika gegen die Alveoläre Echinokokkose N2 - The metacestode larval stage of the fox tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), one of the most lethal zoonosis of the northern hemisphere. The development of metacestode vesicles by asexual multiplication and the almost unrestricted infiltrative growth within the host organs is ensured from a population of undifferentiated, proliferative cells, so-called germinative cells. AE treatment options include surgery, if possible, as well as Benzimidazole-based chemotherapy (BZ). Given that the cellular targets of BZs, the -tubulins, are highly conserved between cestodes and humans, the chemotherapy is associated with considerable side-effects. Therefore, BZ can only be applied in parasitostatic doses and has to be given lifelong. Furthermore, the current anti-AE chemotherapy is ineffective in eliminating the germinative cell population of the parasite, which leads to remission of parasite growth as soon as therapy is discontinued. This work focuses on protein kinases involved in the proliferation and development of the parasite with the intention of developing novel anti-AE therapies. Polo-like kinases (Plks) are important regulators of the eukaryotic cell cycle and are involved in the regulation and formation of the mitotic spindles during the M-phase of the cell cycle. Plks have already been shown to be associated with deregulated cellular growth in human cancers and have been investigated as novel drug targets in the flatworm parasite Schistosoma mansoni. In the first part of this work, the characterisation of a novel and druggable parasite enzyme, EmPlk1, which is homologous to the polo-like kinase 1 (Plk1) of humans and S. mansoni (SmPlk1), is presented. Through in situ hybridisation, it could be demonstrated that emplk1 is specifically expressed in the Echinococcus germinative cells. Upon heterologous expression in the Xenopus oocyte system, EmPlk1 induced germinal vesicle breakdown, thus indicating that it is an active kinase. Furthermore, BI 2536, a compound originally designed to inhibit the human ortholog of EmPlk1, inhibited the EmPlk1 activity at a concentration of 25 nM. In vitro treatment of parasite vesicles with similar concentrations of BI 2536 led to the elimination of the germinative cells from Echinococcus larvae, thus preventing the growth and further development of the parasite. In in vitro cultivation systems for parasite primary cells, BI 2536 effectively inhibited the formation of new metacestode vesicles from germinative cells. Thus, BI 2536 has profound anti-parasitic activities in vitro at concentrations well within the range of plasma levels measured after the administration of safe dosages to patients (50 nM after 24 h). This implies that EmPlk1 is a promising new drug target for the development of novel anti-AE drugs that would specifically affect the parasite’s stem cell population, namely the only parasite cells capable of proliferation. In addition to the chemotherapeutic aspects of this work, the inhibitor BI 2536 could be further used to study the function of stem cells in this model organism, utilising a method of injection of parasite stem cells into metacestode vesicles, for instance, as has been developed in this work. In the second part of this work, a novel receptor tyrosine kinase, the Venus flytrap kinase receptor (EmVKR) of E. multilocularis has been characterised. Members of this class of single-pass transmembrane receptors have recently been discovered in the related trematode S. mansoni and are associated with the growth and differentiation of sporocyst germinal cells and ovocytes. The ortholog receptor in EmVKR is characterised by an unusual domain composition of an extracellular Venus flytrap module (VFT), which shows significant similarity to GABA receptors, such as the GABAB receptor (γ-amino butyric acid type B) and is linked through a single transmembrane domain to an intracellular tyrosine kinase domain with similarities to the kinase domains of human insulin receptors. Based upon the size (5112bp) of emvkr and nucleotide sequence specificities, efforts have been made to isolate the gene from cell culture samples to study the ligand for the activation of this receptor type in Xenopus oocytes. To date, this type of receptor has only been described in invertebrates, thus making it an attractive target for drug screening. In a first trial, the ATP competitive inhibitor AG 1024 was tested in our in vitro cell culture. In conclusion, the EmVKR represents a novel receptor tyrosine kinase in E. multilocularis. Further efforts have to be made to identify the activating ligand of the receptor and its cellular function, which might strengthen the case for EmVKR as a potential drug target. The successful depletion of stem cells in the metacestode vesicle by the Plk1 inhibitor BI 2536 gives rise to optimising the chemical component for EmPlk1 as a new potential drug target. Furthermore, this inhibitor opens a new cell culture technique with high potential to study the cellular behaviour and influencing factors of stem cells in vitro. N2 - Das Verbreitungsgebiet des kleinen Fuchsbandwurms erstreckt sich über die nördliche Hemisphäre und eine Infektion des Menschen verursacht eine meist tödliche verlaufende Parasitose, die alveolaren Echinococcose (AE). Durch infiltratives und asexuelles Wachstum des Larvenstadiums der AE im betroffenen Wirtsorgan kommt es zu einer tödlich verlaufenden Krankheit. Das Wachstum der Metacestoden wird dabei durch undifferenzierte proliferierende Stammzellen, den sog. „germinativen Zellen“ des Fuchsbandwurmes verursacht. Die derzeitigen Behandlungsmöglichkeiten von AE sehen neben einem chirurgischen Eingriff, der in den meisten Fällen nicht möglich ist, nur eine Chemotherapie mit Benzimidazolen (BZ) vor. Die Chemotherapie mit BZ richtet sich dabei gegen die β-Tubuline des Parasiten und ist überwiegend mit einer lebenslangen Behandlung verbunden. Obwohl sich die Behandlungsmöglichkeiten und die Prognose für Patienten seit der Verwendung von Benzimidazolen bedeutsam verbessert haben, kommt es dennoch zu starken Nebenwirkungen und die angewendete Chemotherapie wirkt nur parasitostatisch. Der Grund dafür liegt an der hohen Homologie zwischen den β-Tubulinen des Parasiten und des Menschen, welche die Zielproteine von Benzimidazolen sind. Um die Nebenwirkungen für den Patienten gering zu halten, werden die Benzimidazole nur in Konzentrationen verabreicht, die parasitostatisch wirken, was zu keiner Abtötung des Parasitengewebes führt. Darüber hinaus sind die gegenwärtigen AE-Medikamente nicht wirksam gegen die germinativen Zellen des Parasiten, was zu einem Wiederauftreten des Wachstums von Parasitengewebe führt, sobald die Chemotherapie unterbrochen wird. Die hier vorliegende Arbeit konzentriert sich auf die Entwicklung eines neuen chemotherapeutischen Ansatzes gegen AE und befasst sich mit Proteinkinasen, die einen wesentlichen Einfluss auf die Proliferation und die Differenzierung von Zellen des Parasiten haben. Proteinkinasen, die in direkten Zusammenhang mit den Zellzyklus stehen, sind beispielsweise die Polo-like kinasen (Plk), welche die Bildung von mitotischen Spindelfasern während der M-Phase regulieren. Wie bereits in vorhergehenden Studien gezeigt werden konnte, sind Plks auch an der Entstehung von Krebs beteiligt und daher interessante Ansatzpunkte für die Entwicklung von neuen Chemotherapeutika. Darüber hinaus zeigte sich auch, dass Sie zur Chemotherapie von parasitären Krankheiten Verwendung finden könnten, wie zur Behandlung von Schistosomiasis, welche durch Schistosoma mansoni ausgelöst wird. Der erste Teil dieser Arbeit befasst sich mit der Charakterisierung der Polo-like kinase 1 (Plk1) aus E. multilocularis, die Homologien zur humanen Plk1 und der aus S. mansoni (SmPlk1) aufweist und daher als Ansatzpunkt für eine neuartige chemotherapeutische Behandlung von AE angesehen werden kann. Es konnte gezeigt werden, dass EmPlk1 in germinativen Zellen (Stammzellen) des Parasiten stark exprimiert wird und das es möglich ist, dieses orthologe Protein mit nanomolekularer Konzentration (25 nM) des Plk1 Inhibitors BI 2536 in seiner zellulären Funktion zu hemmen. Darüber hinaus führt die Behandlung in vitro zu einem Verlust von Stammzellen im Larvenstadium von E. multilocularis, was zu einer drastischen Verminderung des Wachstums und der Entwicklung des Parasiten führt. Des Weiteren konnte sehr deutlich gezeigt werden, dass bei Verwendung des Inhibitors BI 2536 in Zellkultursystemen mit „Primärzellen“ (80% Stammzellen) des Parasiten diese nicht mit mehr in der Lage sind in Metacestoden zu regenerieren. Dabei ist entscheidend, dass die verwendeten Konzentrationen des Inhibitors BI 2536 innerhalb der gemessenen Plasmakonzentrationen von Krebspatienten liegen (50 nM nach 48 Stunden). Die Inhibierung der Plk1 wird daher als vielversprechender neuer Ansatzpunkt einer Chemotherapie zur Behandlung der AE angesehen. Die Inhibierung der EmPlk1 hat einen wesentlichen Einfluss auf die Differenzierung von Stammzellen des Parasiten, wodurch das Wachstum und die weitere Entwicklung des Parasiten gehemmt werden. Des Weiteren kann neben der chemotherapeutischen Behandlung der Inhibitor BI2536 auch für das weitere Studium von Stammzellen und deren zelluläre Funktion in E. multilocularis genutzt werden. Dafür wurden erste in vitro Experimente mittels Injektion in stammzellfreie Metacestoden Vesikel durchgeführt. Der zweite Teil dieser Arbeit befasst sich mit einem neuen Transmembranrezeptor in E. multilocularis, der hier als Venus-Fliegenfallen-Rezeptor charakterisiert wird. Dieser Rezeptortyp wurde erst kürzlich in S. mansoni beschrieben und steht im Zusammenhang mit der Entwicklung und dem Wachstum von Keimzellen des Parasiten. Der Rezeptor weist eine ungewöhnliche Zusammensetzung aus einer extrazellulären Venusfliegenfallendomäne (VFT) mit starker Ähnlichkeit zu GABA Rezeptoren auf (γ-amino-Buttersäure Typ B) und ist über eine einzelne Transmembrandomäne mit einer intrazellulären Tyrosinkinasedomäne verbunden, die eine hohe Homologie zu humanen Insulinrezeptoren zeigt. Der lange Genabschnitt (5112bp) von emvkr mit sequenzspezifischen Eigenschaften war schwierig zu klonieren, um eine anschließende Expression in Xenopus Oozyten durchzuführen. Bisher wurde dieser Rezeptor nur in Invertebraten beschrieben und stellt somit einen interessanten Ansatzpunkt für die Entwicklung von neuen Chemotherapeutika dar. In einem ersten Versuch wurde die Wirkung des ATP-Kompetitive Inhibitors AG 1024 in unserer in vitro Zellkultur untersucht. Zusammenfassend wurde die Relevanz von EmVKR als neuartiger Tyrosinkinaserezeptor in E. multilocularis verdeutlicht. In anschließenden Studien sollte die Aktivierung durch Ligandenbindung an den Rezeptor, sowie seine weitere zelluläre Funktion untersucht werden. Diese Erkenntnisse könnten dann eine entscheidende Rolle für die Entwicklung von neuen Medikamenten mit EmVKR spielen. Des Weiteren wurde die erfolgreiche Entfernung von Stammzellen aus Metacestoden Vesikel mit dem Plk1 Inhibitor BI 2536 gezeigt. Dies bietet nun die Option diesen Inhibitor auf das Wirkstoffziel EmPlk1 weiter zu optimieren. Darüber hinaus hat die Verwendung dieses Inhibitors den entscheidenden Zugang für eine neue Zellkulturtechnik ermöglicht, die das Studieren von Stammzellen und deren Einflussfaktoren in vitro bietet. KW - Chemotherapie KW - Echinococcus KW - Fuchsbandwurm KW - Stammzelle KW - Polo-like kinase 1 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113694 ER - TY - JOUR A1 - Kim, Jae Ho A1 - Franck, Julien A1 - Kang, Taewook A1 - Heinsen, Helmut A1 - Ravid, Rivka A1 - Ferrer, Isidro A1 - Cheon, Mi Hee A1 - Lee, Joo-Yong A1 - Yoo, Jong Shin A1 - Steinbusch, Harry W. A1 - Salzet, Michel A1 - Fournier, Isabelle A1 - Park, Young Mok T1 - Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer's disease JF - Scientific Reports N2 - Alzheimer's disease (AD) is the most common form of dementia; however, mechanisms and biomarkers remain unclear. Here, we examined hippocampal CA4 and dentate gyrus subfields, which are less studied in the context of AD pathology, in post-mortem AD and control tissue to identify possible biomarkers. We performed mass spectrometry-based proteomic analysis combined with label-free quantification for identification of differentially expressed proteins. We identified 4,328 proteins, of which 113 showed more than 2-fold higher or lower expression in AD hippocampi than in control tissues. Five proteins were identified as putative AD biomarkers (MDH2, PCLO, TRRAP, YWHAZ, and MUC19 isoform 5) and were cross-validated by immunoblotting, selected reaction monitoring, and MALDI imaging. We also used a bioinformatics approach to examine upstream signalling interactions of the 113 regulated proteins. Five upstream signalling (IGF1, BDNF, ZAP70, MYC, and cyclosporin A) factors showed novel interactions in AD hippocampi. Taken together, these results demonstrate a novel platform that may provide new strategies for the early detection of AD and thus its diagnosis. KW - imaging mass spectrometry KW - neuron navigator 3 KW - dentate gyrus KW - growth factor KW - mouse model KW - neurotrophic factor KW - entorhinal cortex KW - factor expression KW - oxidative stress KW - memory deficits Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151727 VL - 5 IS - 11138 ER - TY - JOUR A1 - Neudecker, Jens A1 - Malzahn, Uwe A1 - Heuschmann, Peter A1 - Behrens, Uwe A1 - Walles, Thorsten T1 - Pulmonary wedge resection plus parietal pleurectomy (WRPP) versus parietal pleurectomy (PP) for the treatment of recurrent primary pneumothorax (WOPP trial): study protocol for a randomized controlled trial JF - Trials N2 - Background For the surgical treatment of recurrent primary spontaneous pneumothoraces (rPSP) different operative therapies are applied to achieve permanent freedom from recurrence. Methods/design This multicenter clinical trial evaluates the long-term results of two commonly applied surgical techniques for the treatment of rPSP. Based on the inclusion and exclusion criteria, and after obtaining the patients’ informed consent, participants are randomized into the two surgical treatment arms: pulmonary wedge resection plus parietal pleurectomy (WRPP) or parietal pleurectomy alone (PP). Consecutively, all study participants will be followed up for two years to evaluate the surgical long-term effect. The primary efficacy endpoint is the recurrence rate of pneumothorax within 24 months after surgery. The calculated sample size is 360 patients (n = 180 per treatment arm) to prove superiority of one of the two treatments. So far, 22 surgical sites have submitted their declaration of commitment, giving the estimated number of participating patients. Discussion A prospective randomized clinical trial has been started to compare two established surgical therapies to evaluate the long-term results regarding recurrence rates. Furthermore, cost of treatment, and influence on the perioperative morbidity and mortality as well as on quality of life are analyzed. If the study reveals equivalence for both surgical techniques, unnecessary pulmonary resections could be avoided. KW - multicenter KW - prospective randomized trial KW - pulmonary wedge resection KW - parietal pleurectomy KW - recurrent primary pneumothorax Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145869 VL - 16 ER - TY - JOUR A1 - Herweg, Jo-Ana A1 - Hansmeier, Nicole A1 - Otto, Andreas A1 - Geffken, Anna C. A1 - Subbarayal, Prema A1 - Prusty, Bhupesh K. A1 - Becher, Dörte A1 - Hensel, Michael A1 - Schaible, Ulrich E. A1 - Rudel, Thomas A1 - Hilbi, Hubert T1 - Purification and proteomics of pathogen-modified vacuoles and membranes JF - Frontiers in Cellular and Infection Microbiology N2 - Certain pathogenic bacteria adopt an intracellular lifestyle and proliferate in eukaryotic host cells. The intracellular niche protects the bacteria from cellular and humoral components of the mammalian immune system, and at the same time, allows the bacteria to gain access to otherwise restricted nutrient sources. Yet, intracellular protection and access to nutrients comes with a price, i.e., the bacteria need to overcome cell-autonomous defense mechanisms, such as the bactericidal endocytic pathway. While a few bacteria rupture the early phagosome and escape into the host cytoplasm, most intracellular pathogens form a distinct, degradation-resistant and replication-permissive membranous compartment. Intracellular bacteria that form unique pathogen vacuoles include Legionella, Mycobacterium, Chlamydia, Simkania, and Salmonella species. In order to understand the formation of these pathogen niches on a global scale and in a comprehensive and quantitative manner, an inventory of compartment-associated host factors is required. To this end, the intact pathogen compartments need to be isolated, purified and biochemically characterized. Here, we review recent progress on the isolation and purification of pathogen-modified vacuoles and membranes, as well as their proteomic characterization by mass spectrometry and different validation approaches. These studies provide the basis for further investigations on the specific mechanisms of pathogen-driven compartment formation. KW - spectrometry-based proteomics KW - Mycobacterium tuberculosis KW - Chlamydia KW - Salmonella KW - bacterium Legionella pneumophila KW - endocytic multivesicular bodies KW - phagosome maturation arrest KW - III secretion system KW - endoplasmic reticulum KW - Chlamydia trachomatis KW - Simkania negevensis KW - intracellular bacteria KW - host pathogen interactions KW - immuno-magnetic purification KW - Legionella KW - Mycobacterium KW - Simkania KW - pathogen vacuole Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151823 VL - 5 IS - 48 ER - TY - JOUR A1 - Klink, Thomas A1 - Sauer, Johannes A1 - Körber, Norbert J A1 - Grehn, Franz A1 - Much, Martin M A1 - Thederan, Luisa A1 - Matlach, Juliane A1 - Salgado, Josefina Parente T1 - Quality of life following glaucoma surgery: canaloplasty versus trabeculectomy JF - Clinical Ophthalmology N2 - Purpose: To evaluate quality of life (QoL) with a new questionnaire after canaloplasty (CP) and trabeculectomy (TE). Patients and methods: We assessed outcomes of surgery, rate of revision surgeries, patients’ mood, and influence of postoperative care on QoL, surgery interference with daily activities, and postsurgical complaints. Patients completed the QoL questionnaire 24 months after surgery. Results: Patients who underwent CP (n=175) were compared to TE patients (n=152). In the CP group, 57% of patients expressed high satisfaction, while 41% of patients in the TE group said they were highly satisfied. The satisfaction difference was statistically significant (P=0.034). Significantly fewer second surgeries were needed after CP (8% CP versus 35% TE, P<0.001). Patients were more positive in the CP group (54% CP versus 37% TE, P<0.009). Stress related to postoperative care was lower in the CP group compared to the TE group (14% versus 46%). Difficulties with activities of daily living, such as reading, were much lower or even nonexistent after CP, and complaints like eye burning or stinging were significantly lower in the CP group. Conclusions: Compared with TE, CP is associated with less QoL impairment and higher patient satisfaction after surgery. However, long-term data on intraocular pressure reduction after surgery are needed to confirm long-term patient satisfaction with this surgery. KW - glaucoma KW - postoperative care KW - glaucoma surgery KW - non-penetrating glaucoma surgery Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149520 VL - 9 ER - TY - JOUR A1 - Lewitzki, Victor A1 - Andratschke, Nicolaus A1 - Kuhnt, Thomas A1 - Hildebrandt, Guido T1 - Radiation myelitis after hypofractionated radiotherapy with concomitant gefitinib JF - Radiation Oncology N2 - We describe the case of a 71-year-old Caucasian female with primary disseminated non-small cell cancer of the lung, presented for palliative radiotherapy of metastatic spread to the 9th and 11th thoracic vertebrae without intramedullary growth. Palliative radiotherapy with daily fractions of 3 Gy and a cumulative dose of 36 Gy to thoracic vertebrae 8-12 was performed. The patient received concomitantly 250 mg gefitinib daily. After a latent period of 16 months, the patient developed symptoms of myelitis. Magnetic resonance imaging (MRI) did not reveal any bony or intraspinal tumor progression, but spinal cord signal alteration. No response to steroids was achieved. The neurological symptoms were progressive in August 2013 with the right leg being completely plegic. The left leg was incompletely paralyzed. Deep and superficial sensitivity was also diminished bilaterally. The patient was completely urinary and anally incontinent. Contrary to the clinical findings, a follow-up MRI (July 2013) showed amelioration of the former signal alterations in the spinal cord. The diagnosis of paraneoplastic myelopathy was refuted by a negative test for autologous antibodies. At the last clinical visit in May 2014, the neurological symptoms were stable. The last tumor-specific treatment the patient is receiving is erlotinib 125 mg/d. We reviewed the literature and found no reported cases of radiation myelopathy after the treatment in such a setting. The calculated probability of such complication after radiotherapy alone is statistically measurable at the level of 0.02%. We suppose that gefitinib could also play a role in the development of this rare complication. KW - radiation myelitis KW - concomitant radiotherapy KW - gefitinib Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175443 VL - 10 IS - 29 ER - TY - JOUR A1 - Chen, Xinyu A1 - Werner, Rudolf A. A1 - Javadi, Mehrbod S. A1 - Maya, Yoshifumi A1 - Decker, Michael A1 - Lapa, Constantin A1 - Herrmann, Ken A1 - Higuchi, Takahiro T1 - Radionuclide imaging of neurohormonal system of the heart JF - Theranostics N2 - Heart failure is one of the growing causes of death especially in developed countries due to longer life expectancy. Although many pharmacological and instrumental therapeutic approaches have been introduced for prevention and treatment of heart failure, there are still limitations and challenges. Nuclear cardiology has experienced rapid growth in the last few decades, in particular the application of single photon emission computed tomography (SPECT) and positron emission tomography (PET), which allow non-invasive functional assessment of cardiac condition including neurohormonal systems involved in heart failure; its application has dramatically improved the capacity for fundamental research and clinical diagnosis. In this article, we review the current status of applying radionuclide technology in non-invasive imaging of neurohormonal system in the heart, especially focusing on the tracers that are currently available. A short discussion about disadvantages and perspectives is also included. KW - SPECT KW - radiotracer KW - heart failure KW - cardiac neurohormonal system KW - nuclear cardiology KW - PET Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149205 VL - 5 IS - 6 ER - TY - JOUR A1 - Schottdorf, Manuel A1 - Keil, Wolfgang A1 - Coppola, David A1 - White, Leonard E. A1 - Wolf, Fred T1 - Random Wiring, Ganglion Cell Mosaics, and the Functional Architecture of the Visual Cortex JF - PLoS Computational Biology N2 - The architecture of iso-orientation domains in the primary visual cortex (V1) of placental carnivores and primates apparently follows species invariant quantitative laws. Dynamical optimization models assuming that neurons coordinate their stimulus preferences throughout cortical circuits linking millions of cells specifically predict these invariants. This might indicate that V1's intrinsic connectome and its functional architecture adhere to a single optimization principle with high precision and robustness. To validate this hypothesis, it is critical to closely examine the quantitative predictions of alternative candidate theories. Random feedforward wiring within the retino-cortical pathway represents a conceptually appealing alternative to dynamical circuit optimization because random dimension-expanding projections are believed to generically exhibit computationally favorable properties for stimulus representations. Here, we ask whether the quantitative invariants of V1 architecture can be explained as a generic emergent property of random wiring. We generalize and examine the stochastic wiring model proposed by Ringach and coworkers, in which iso-orientation domains in the visual cortex arise through random feedforward connections between semi-regular mosaics of retinal ganglion cells (RGCs) and visual cortical neurons. We derive closed-form expressions for cortical receptive fields and domain layouts predicted by the model for perfectly hexagonal RGC mosaics. Including spatial disorder in the RGC positions considerably changes the domain layout properties as a function of disorder parameters such as position scatter and its correlations across the retina. However, independent of parameter choice, we find that the model predictions substantially deviate from the layout laws of iso-orientation domains observed experimentally. Considering random wiring with the currently most realistic model of RGC mosaic layouts, a pairwise interacting point process, the predicted layouts remain distinct from experimental observations and resemble Gaussian random fields. We conclude that V1 layout invariants are specific quantitative signatures of visual cortical optimization, which cannot be explained by generic random feedforward-wiring models. KW - placental mammal KW - simple receptive-fields KW - ocular dominance columns KW - lateral geniculate-nucleus KW - direction selectivity KW - tree shrew KW - orientation columns KW - K-PG radiation KW - monkey striate cortex KW - ancestor KW - cortical magnification factor Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138879 VL - 11 IS - 11 ER - TY - JOUR A1 - Käthner, Ivo A1 - Kübler, Andrea A1 - Halder, Sebastian T1 - Rapid P300 brain-computer interface communication with a head-mounted display JF - Frontiers in Neuroscience N2 - Visual ERP (P300) based brain-computer interfaces (BCIs) allow for fast and reliable spelling and are intended as a muscle-independent communication channel for people with severe paralysis. However, they require the presentation of visual stimuli in the field of view of the user. A head-mounted display could allow convenient presentation of visual stimuli in situations, where mounting a conventional monitor might be difficult or not feasible (e.g., at a patient's bedside). To explore if similar accuracies can be achieved with a virtual reality (VR) headset compared to a conventional flat screen monitor, we conducted an experiment with 18 healthy participants. We also evaluated it with a person in the locked-in state (LIS) to verify that usage of the headset is possible for a severely paralyzed person. Healthy participants performed online spelling with three different display methods. In one condition a 5 x 5 letter matrix was presented on a conventional 22 inch TFT monitor. Two configurations of the VR headset were tested. In the first (glasses A), the same 5 x 5 matrix filled the field of view of the user. In the second (glasses B), single letters of the matrix filled the field of view of the user. The participant in the LIS tested the VR headset on three different occasions (glasses A condition only). For healthy participants, average online spelling accuracies were 94% (15.5 bits/min) using three flash sequences for spelling with the monitor and glasses A and 96% (16.2 bits/min) with glasses B. In one session, the participant in the LIS reached an online spelling accuracy of 100% (10 bits/min) using the glasses A condition. We also demonstrated that spelling with one flash sequence is possible with the VR headset for healthy users (mean: 32.1 bits/min, maximum reached by one user: 71.89 bits/min at 100% accuracy). We conclude that the VR headset allows for rapid P300 BCI communication in healthy users and may be a suitable display option for severely paralyzed persons. KW - speller performance KW - face perception KW - stimulus KW - rapid BCI KW - locked-in state KW - P300 KW - head-mounted display KW - brain-computer interface Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148520 VL - 9 IS - 207 ER - TY - JOUR A1 - Murakawa, Yasuhiro A1 - Hinz, Michael A1 - Mothes, Janina A1 - Schuetz, Anja A1 - Uhl, Michael A1 - Wyler, Emanuel A1 - Yasuda, Tomoharu A1 - Mastrobuoni, Guido A1 - Friedel, Caroline C. A1 - Dölken, Lars A1 - Kempa, Stefan A1 - Schmidt-Supprian, Marc A1 - Blüthgen, Nils A1 - Backofen, Rolf A1 - Heinemann, Udo A1 - Wolf, Jana A1 - Scheidereit, Claus A1 - Landthaler, Markus T1 - RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-\(\kappa\)B pathway JF - Nature Communications N2 - The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNF\(\alpha\) mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ~3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-\(\kappa\)B pathway regulators such as I\(\kappa\)B\(\alpha\) and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3'UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with I\(\kappa\)B kinase and NF-\(\kappa\)B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-\(\kappa\)B pathway. KW - large gene lists KW - decay KW - identification KW - stress KW - binding protein KW - RQQ domain KW - autoimmunity KW - complex KW - degradation KW - motifs Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151596 VL - 6 IS - 7367 ER - TY - JOUR A1 - Singh, Amit K. A1 - Kingston, Joseph J. A1 - Gupta, Shishir K. A1 - Batra, Harsh V. T1 - Recombinant Bivalent Fusion Protein rVE Induces CD4+ and CD8+ T-Cell Mediated Memory Immune Response for Protection Against Yersinia enterocolitica Infection JF - Frontiers in Microbiology N2 - Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y pestis LcrV (100-270 aa) and YopE (50-213 aa) proteins conferred complete passive and active protection against lethal Y enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y enterocolitica 8081 rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up regulation of both Th1 (INF-\(\alpha\), IFN-\(\gamma\), IL 2, and IL 12) and Th2 (IL 4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens. KW - I-tasser KW - Yersinia enterocolitica KW - memory immune responses KW - cytokine profiling KW - CD8+T cells KW - CD4+T cells KW - recombinant protein rVE KW - resistance KW - pneumonic plague KW - pestis infection KW - nonhuman-primates KW - III secretion KW - V-antigen KW - mice KW - vaccine Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136114 VL - 6 IS - 1407 ER - TY - JOUR A1 - Biegstraaten, Marieke A1 - Arngrímsson, Reynir A1 - Barbey, Frederic A1 - Boks, Lut A1 - Cecchi, Franco A1 - Deegan, Patrick B A1 - Feldt-Rasmussen, Ulla A1 - Geberhiwot, Tarekegn A1 - Germain, Dominique P A1 - Hendriksz, Chris A1 - Hughes, Derralynn A A1 - Kantola, Ilkka A1 - Karabul, Nesrin A1 - Lavery, Christine A1 - Linthorst, Gabor E A1 - Mehta, Atul A1 - van de Mheen, Erica A1 - Oliveira, João P A1 - Parini, Rossella A1 - Ramaswami, Uma A1 - Rudnicki, Michael A1 - Serra, Andreas A1 - Sommer, Claudia A1 - Sunder-Plassmann, Gere A1 - Svarstad, Einar A1 - Sweeb, Annelies A1 - Terryn, Wim A1 - Tylki-Szymanska, Anna A1 - Tøndel, Camilla A1 - Vujkovac, Bojan A1 - Weidemann, Frank A1 - Wijburg, Frits A A1 - Woolfson, Peter A1 - Hollak, Carla EM T1 - Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document JF - Orphanet Journal of Rare Diseases N2 - Introduction: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. Methods: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. Results: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m\(^{2}\)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. Conclusion: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations. KW - Fabry disease KW - enzyme replacement therapy KW - recommendations KW - Delphi procedure Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175374 VL - 10 IS - 36 ER - TY - JOUR A1 - Hefner, Jochen A1 - Csef, Herbert A1 - Frantz, Stefan A1 - Glatter, Nina A1 - Warrings, Bodo T1 - Recurrent Tako-Tsubo cardiomyopathy (TTC) in a pre-menopausal woman: late sequelae of a traumatic event? JF - BMC Cardiovascular Disorders N2 - Background “Tako-Tsubo cardiomyopathy” (TTC) is a syndrome characterized by left ventricular (LV) wall motion abnormalities, usually without coronary artery disease, mimicking the diagnosis of acute coronary syndrome. It most often affects post-menopausal women and TTC tends to run a benign course with very low rates of recurrence, complications or mortality. The condition is also called “stress-induced cardiomyopathy” because acute physical or emotional stress appears to be frequently related to its onset. The pathogenic role of premorbid or comorbid psychiatric illnesses has been discussed controversially. For the first time, we present a case of fourfold recurrent TTC with severe complications in a pre-menopausal woman. Furthermore, a long history of flaring posttraumatic stress symptoms anteceded the first event. Case presentation A 43-year old, pre-menopausal Caucasian woman was hospitalized with symptoms of acute coronary syndrome. Clinical examination revealed hypokinetic wall motion in the apical ventricular region with no signs of coronary artery disease and diagnosis of TTC was established. She experienced recurrence three times within the following ten months, which led to thrombembolism and myocardial scarring among others. The circumstances of chronic distress were striking. 16 years ago she miscarried after having removed a myoma according to her doctor’s suggestion. Since then, she has suffered from symptoms of posttraumatic distress which peaked annually at the day of abortion. Chronic distress became even more pronounced after the premature birth of a daughter some years later. The first event of TTC occurred after a family dispute about parenting. Conclusion This is the first case report of fourfold TTC in a pre-menopausal woman. From somatic perspectives, the course of the disease with recurrences and complications underlines the fact that TTC is not entirely benign. Furthermore, it is the first case report of long lasting symptoms of traumatic stress anteceding TTC. Close connections between adrenergic signaling and late onset of clinical stress symptoms are well known in the psychopathology of traumatization. Although larger clinical trials are needed to elucidate possible interactions of premorbid psychiatric illnesses and TTC, cardiologists should be vigilant especially in cases of recurrent TTC. KW - recurrent Tako-Tsubo cardiomyopathy KW - chronic distress KW - gene-environment interaction KW - comprehensive psychosomatic assessment Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124949 VL - 15 IS - 3 ER - TY - JOUR A1 - Preising, Christina A1 - Schneider, Reinhard A1 - Bucher, Michael A1 - Gekle, Michael A1 - Sauvant, Christoph T1 - Regulation of expression of renal organic anion transporters OAT1 and OAT3 in a model of ischemia/reperfusion injury JF - Cellular Physiology and Biochemistry N2 - Background: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI) is mediated by COX metabolites and this suppression might be critically involved in renal damage. Methods: (i) Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R) was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6) and hOAT3 (SCL22A8) were cloned into a reporter plasmid, transfected into HEK cells and (ii) transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. Results: By using inhibitors of PKA (H89) and PLC (U73122), antagonists of E prostanoid receptor type 2 (AH6809) and type 4 (L161,982), we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist) or TCS2510 (EP4 agonist) to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125) and COX2 (SC560) were also applied. Conclusion: Our data show (a) that COX1 metabolites are involved in the regulation of renal organic anion transport(ers) after I/R via the EP4 receptor and (b) that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c) hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well. KW - opossum kidney cells KW - prostaglandin e2 KW - reperfusion KW - transport experiments KW - translation KW - reporter gen assay KW - cloning of putative human promoter sequence KW - regulation of expression KW - OAT1 KW - OAT3 KW - OK cells KW - ischemic acute kidney injury model KW - HEK cells KW - ischemia KW - down regulation KW - nitric oxide KW - cellular physiology KW - cortical OAT1 KW - blood flow Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144504 VL - 37 IS - 1 ER - TY - THES A1 - Jänicke, Laura Annika T1 - Regulation of MYC Activity by the Ubiquitin-Proteasome System T1 - Regulation der MYC Aktivität durch das Ubiquitin-Proteasom-System N2 - The oncogenic MYC protein is a transcriptional regulator of multiple cellular processes and is aberrantly activated in a wide range of human cancers. MYC is an unstable protein rapidly degraded by the ubiquitin-proteasome system. Ubiquitination can both positively and negatively affect MYC function, but its direct contribution to MYC-mediated transactivation remained unresolved. To investigate how ubiquitination regulates MYC activity, a non-ubiquitinatable MYC mutant was characterized, in which all lysines are replaced by arginines (K-less MYC). The absence of ubiquitin-acceptor sites in K-less MYC resulted in a more stable protein, but did not affect cellular localization, chromatin-association or the ability to interact with known MYC interaction partners. Unlike the wild type protein, K-less MYC was unable to promote proliferation in immortalized mammary epithelial cells. RNA- and ChIP-Sequencing analyses revealed that, although K-less MYC was present at MYC-regulated promoters, it was a weaker transcriptional regulator. The use of K-less MYC, a proteasomal inhibitor and reconstitution of individual lysine residues showed that proteasomal turnover of MYC is required for MYC target gene induction. ChIP-Sequencing of RNA polymerase II (RNAPII) revealed that MYC ubiquitination is dispensable for RNAPII recruitment and transcriptional initiation but is specifically required to promote transcriptional elongation. Turnover of MYC is required to stimulate histone acetylation at MYC-regulated promoters, which depends on a highly conserved region in MYC (MYC box II), thereby enabling the recruitment of BRD4 and P-TEFb and the release of elongating RNAPII from target promoters. Inhibition of MYC turnover enabled the identification of an intermediate in MYC-mediated transactivation, the association of MYC with the PAF complex, a positive elongation factor, suggesting that MYC acts as an assembly factor transferring elongation factors onto RNAPII. The interaction between MYC and the PAF complex occurs via a second highly conserved region in MYC’s amino terminus, MYC box I. Collectively, the data of this work show that turnover of MYC coordinates histone acetylation with recruitment and transfer of elongation factors on RNAPII involving the cooperation of MYC box I and MYC box II. N2 - Der Transkriptionsfaktor MYC ist an der Regulation einer Vielzahl biologischer Prozesse beteiligt ist und spielt bei der Tumorentstehung und des Tumorwachstum eine entscheidende Rolle. MYC ist ein kurzlebiges Protein, das durch das Ubiquitin-Proteasom-System abgebaut wird. Die Ubiquitinierung von MYC hat auch einen stimulierenden Einfluss auf dessen transkriptionelle Aktivität. Dabei blieb jedoch der Mechanismus, der dieser Beobachtung zugrunde liegt, bislang ungeklärt. Um den direkten Einfluss von Ubiquitinierung auf die Aktivität von MYC zu untersuchen, wurde in der vorliegenden Arbeit eine MYC Mutante analysiert, in der alle Lysine zu Argininen mutiert wurden (K-less MYC). Die Mutation der Ubiquitin-Verknüpfungsstellen resultierte in einem stabileren Protein, hatte jedoch keinen Einfluss auf die zelluläre Lokalisation oder Assoziation mit bekannten Interaktionspartnern. Im Vergleich zu Wildtyp (WT) MYC war K-less MYC jedoch in der Vermittlung MYC-induzierter biologischer Phänotypen stark beeinträchtigt. Mittels RNA- und ChIP-Sequenzierungen konnte gezeigt werden, dass K-less MYC zwar an MYC-regulierte Promotoren bindet, in der transkriptionellen Aktivität aber stark beeinträchtigt ist und diese Zielgene nicht aktivieren kann. Dabei war K-less MYC noch in der Lage, RNA Polymerase II (RNAPII) zu den Zielpromotoren zu rekrutieren und die Transkription dort zu initiieren, jedoch war der Übergang zur Elongation blockiert. Die Verwendung eines Proteasom-Inhibitors sowie die Rekonstitution einzelner Lysine in K-less MYC zeigten, dass der proteasomale Abbau von MYC für die Aktivierung von Zielgenen benötigt wird. Der proteasomale Abbau ist für die Histon-Acetylierung von Bedeutung, die von einer hoch konservieren Region in MYC, der MYC Box II, abhängt. Durch die WT MYC-vermittelte Induktion der Histon-Acetylierung können folglich die Proteine BRD4 und P-TEFb an die Promotoren rekrutiert werden. Diese Proteine spielen bei dem Übergang der initiierenden RNAPII zur elongierenden RNAPII eine essentielle Rolle. Darüber hinaus ermöglichte die Inhibition des MYC Abbaus die Identifizierung eines Zwischenschritts der MYC-abhängigen Transaktivierung: die Assoziation von MYC mit dem positiven Elongationskomplex, dem PAF-Komplex. Dieser wird über eine zweite hochkonservierte Region in MYC, der MYC Box I, rekrutiert. Somit kann angenommen werden, dass MYC als eine Verbindungsstelle fungiert, die positive Elongationsfaktoren auf die RNAPII transferiert. Zusammenfassend resultieren die Daten dieser Arbeit in einem Model, nach dem der proteasomale Abbau von MYC die Histon-Acetylierung mit der Rekrutierung und dem Transfer von Elongationsfaktoren auf die RNAPII koordiniert, was der Kooperation von MYC Box I und MYC Box II bedarf. KW - Myc KW - Ubiquitinierung KW - Transkription KW - RNS-Polymerase II KW - Elongation (Transkription) KW - Proteasomaler Abbau Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123339 ER - TY - JOUR A1 - Zhang, Yi A1 - Lee, Chil-Woo A1 - Wehner, Nora A1 - Imdahl, Fabian A1 - Svetlana, Veselova A1 - Weiste, Christoph A1 - Dröge-Laser, Wolfgang A1 - Deeken, Rosalia T1 - Regulation of Oncogene Expression in T-DNA-Transformed Host Plant Cells JF - PLoS Pathogens N2 - Virulent Agrobacterium tumefaciens strains integrate their T-DNA into the plant genome where the encoded agrobacterial oncogenes are expressed and cause crown gall disease. Essential for crown gall development are IaaH (indole-3-acetamide hydrolase), IaaM (tryptophan monooxygenase) and Ipt (isopentenyl transferase), which encode enzymes for the biosynthesis of auxin (IaaH, IaaM) and cytokinin (Ipt). Although these oncogenes are well studied as the tumor-inducing principle, nothing is known about the regulation of oncogene expression in plant cells. Our studies show that the intergenic regions (IGRs) between the coding sequences (CDS) of the three oncogenes function as promoters in plant cells. These promoters possess a eukaryotic sequence organization and cis-regulatory elements for the binding of plant transcription factors. WRKY18, WRKY40, WRKY60 and ARF5 were identified as activators of the Ipt promoter whereas IaaH and IaaM is constitutively expressed and no transcription factor further activates their promoters. Consistent with these results, the wrky triple mutant plants in particular, develops smaller crown galls than wild-type and exhibits a reduced Ipt transcription, despite the presence of an intact ARF5 gene. WRKY40 and WRKY60 gene expression is induced by A. tumefaciens within a few hours whereas the ARF5 gene is transcribed later during crown gall development. The WRKY proteins interact with ARF5 in the plant nucleus, but only WRKY40 together with ARF5 synergistically boosts the activation of the Ipt promoter in an auxin-dependent manner. From our data, we propose that A. tumefaciens initially induces WRKY40 gene expression as a pathogen defense response of the host cell. The WRKY protein is recruited to induce Ipt expression, which initiates cytokinin-dependent host cell division. With increasing auxin levels triggered by ubiquitous expression of IaaH and IaaM, ARF5 is activated and interacts with WRKY40 to potentiate Ipt expression and balance cytokinin and auxin levels for further cell proliferation. KW - luminescence KW - oncogenes KW - agrobacterium tumefaciens KW - transcription factors KW - auxins KW - gene expression KW - cytokinins KW - plant cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125256 VL - 11 IS - 1 ER - TY - THES A1 - Rikkala, Prashanth Reddy T1 - Regulation of the Na+-D-glucose cotransporter SGLT1 in the small intestine in response to bariatric surgery and peptides derived from protein RS1 (RSC1A1) T1 - Regulation des Na+-D-Glucose Kotranporters SGLT1 im Dünndarm nach bariatrischen Operation und durch von Protein RS1 (RSC1A1) abgeleitete Peptide N2 - Bariatric surgery represents the first-line treatment for morbid obesity, resulting in weight loss and improved diabetes control. The positive effect of bariatric surgery on type-2 diabetes is unclear. Increased secretion of insulin regulating enterohormone glucagon-like-peptide 1 (GLP-1) has been observed in rats with experimental type 2-like diabetes following duodenal-jejunal bypass (DJB) and ileal transposition (IT). Sodium dependent glucose co-transporter (SGLT1) is involved in the secretion of GLP-1 that in turn regulates insulin secretion. In the present study, an attempt was made to elucidate the impact of DJB and IT on SGLT1 mediated glucose transport. Transport measurements using phlorizin inhibited uptake of SGLT1-specific glucose analogue [14C] α-Methyl-D-glucopyranoside (AMG) were performed to determine the changes in SGLT1 transport upon these surgical procedures. The data indicated that DJB decreased SGLT1-mediated glucose absorption in the small intestine which contributes to the body-weight independent improvement of type 2 diabetes. However, IT did not change the SGLT1-mediated glucose transport. Immunohistochemical analysis revealed that in IT, the transposed ileum showed increased diameter, increased villi length and increased number of GLP-1 secreting L-cells. The weight-independent improvement in glycemic control after IT is not related to SGLT1-mediated glucose absorption but may be linked to increased GLP-1 secretion. Along with this, the study also focused on the regulation of SGLT1 by several RS1 derived tripeptides in mouse and human intestinal tissues (ex vivo). Phlorizin inhibited uptake of AMG was measured without and with tripeptides. QEP and thiophosphorylated QSP down-regulated SGLT1 activity in small intestine in a concentration-dependent manner. Among the tested tripeptides, QEP showed higher activity and further analysis in various species demonstrated its universal role in SGLT1 regulation. The data thus indicates that RS1 derived tripeptides QEP and thiophosphorylated QSP may be employed for the treatment of type 2 diabetes. N2 - Bariatrische Operationen repräsentieren die Behandlung erster Wahl bei krankhafter Fettleibigkeit, resultierend in Gewichtsverlust und verbesserter Diabetes-Kontrolle. Der positive Effekt bariatrischer Operationen auf den Typ-2 Diabetes ist unklar. Erhöhte Sekretion von Insulin, welches das Enterohormon „Glucagon-like-peptide 1“ (GLP-1) reguliert, wurde beobachtet bei Ratten mit experimentellem Typ 2-ähnlichem Diabetes nach duodenalem-jejunalem Bypass (DJB) und ilealer Transposition (IT). Der Natrium-abhängige Glucose Cotransporter (SGLT1) ist beteiligt an der Sekretion von GLP-1, das wiederum die Insulin-Sekretion reguliert. In der vorliegenden Studie wurde der Versuch unternommen, die Bedeutung von DJB und IT für den durch SGLT1 vermittelten Glucose-Transport aufzuklären. Transportmessungen der durch Phlorizin hemmbaren Aufnahme des SGLT1-spezifischen Glucose-Analogs [14C] α-Methyl-D-glucopyranosid (AMG) wurden durchgeführt, um die durch diese chirurgischen Eingriffe bedingten Änderungen des Transports durch SGLT1 zu bestimmen. Die Daten deuten darauf hin, dass DJB die SGLT1-vermittelte Glucose Absorption im Dünndarm verringert, was zu einer körpergewichts-unabhängigen Verbesserung des Diabetes Typ 2 beiträgt. Aber IT veränderte den SGLT1-vermittelten Glucose-Transport nicht. Immunhistochemische Analysen zeigten, dass bei IT das transponierte Ileum einen vergrößerten Durchmesser, eine erhöhte Länge der Villi und eine erhöhte Anzahl der GLP-1 sekretierenden L-Zellen aufwies. Die gewichtsunabhängige Verbesserung der glykämischen Kontrolle nach IT steht nicht im Zusammenhang mit der durch SGLT1-vermittelten Glucose-Absorption, sondern könnte verbunden sein mit einer erhöhten GLP-1 Sekretion. Damit einhergehend fokussiert sich die Studie auch auf die Regulation des SGLT1 durch verschiedene, von RS1 abgeleitete Tripeptide in Darm-Gewebe von Maus und Mensch (ex vivo). Die phlorizin-hemmbare Aufnahme von AMG wurde gemessen mit und ohne Tripeptide. QEP und thiophosphoryliertes QSP regulierten die SGLT1-Aktivität herunter im Dünndarm auf eine konzentrationsabhängige Weise. Unter den getesteten Tripeptiden zeigte QEP eine höhere Aktivität und weitere Analysen in verschiedenen Spezies zeigten seine universelle Rolle in der SGLT1-Regulation.Die Daten zeigen daher, dass die von RS1 abgeleiteten Tripeptide QEP und thiophosporyliertes QSP eingesetzt werden könnten zur Behandlung von Typ2 Diabetes. KW - Glucosetransportproteine KW - Fettsucht KW - Duodenal Jejunal Bypass KW - Ileal Trasposition KW - RS1 derived peptides KW - Chirurgie KW - Diabetes mellitus KW - Typ 2 KW - Bariatric surgery KW - RS1 Peptides Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130608 ER - TY - JOUR A1 - Lv, Xiaoqun A1 - Zhang, Lingyun A1 - Zhu, Yanyan A1 - Said, Harun M. A1 - Shi, Jimin A1 - Xu, Guoxiong T1 - Regulative effect of Nampt on tumor progression and cell viability in human colorectal cancer JF - Journal of Cancer N2 - Colorectal cancer (CRC) is the third most common cancer disease. Here we examined Nampt expression in patients with CRC and the effect of Nampt on cell viability in CRC cells. Nampt protein was overexpressed in colorectal adenoma as well as colorectal carcinoma. The immunoreactive staining of Nampt was negative in the adjacent normal colorectal tissue, weak in colorectal adenoma, and strong in colorectal carcinoma, which may represent tumor progression. Further evaluation of clinical data showed that Nampt expression was not correlated with the clinicopathological characteristics of CRC. Additionally, our in vitro studies demonstrated that Nampt promotes CRC cell viability, whereas the Nampt inhibitor FK866 suppressed CRC cell viability, which was in concordance with the previous studies in other cancer cells. Treatment with Nampt-siRNA reduced the Nampt protein expression resulting in the inhibition of the cell viability of HCT116 and Caco2. Thus, the involvement of Nampt in cell growth indicates that Nampt may play an important role in colorectal tumorigenesis. As a consequence, our results suggest that Nampt may be considered as a progression marker of colorectal tumor and a potentially therapeutic target for the treatment of CRC. KW - nicotinamide phosphoribosyltransferase KW - signaling pathways KW - gastric cancer KW - overexpression KW - cell proliferation KW - tumor biomarker KW - adenocarcinoma KW - Nampt KW - visfatin KW - PBEF KW - breast cancer KW - prognostic value KW - visfatin levels KW - inhibitor KW - expression KW - adipocytokines Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144516 VL - 6 IS - 9 ER - TY - JOUR A1 - Geffers, Martha A1 - Groll, Jürgen A1 - Gbureck, Uwe T1 - Reinforcement strategies for load-bearing calcium phosphate biocements JF - Materials N2 - Calcium phosphate biocements based on calcium phosphate chemistry are well-established biomaterials for the repair of non-load bearing bone defects due to the brittle nature and low flexural strength of such cements. This article features reinforcement strategies of biocements based on various intrinsic or extrinsic material modifications to improve their strength and toughness. Altering particle size distribution in conjunction with using liquefiers reduces the amount of cement liquid necessary for cement paste preparation. This in turn decreases cement porosity and increases the mechanical performance, but does not change the brittle nature of the cements. The use of fibers may lead to a reinforcement of the matrix with a toughness increase of up to two orders of magnitude, but restricts at the same time cement injection for minimal invasive application techniques. A novel promising approach is the concept of dual-setting cements, in which a second hydrogel phase is simultaneously formed during setting, leading to more ductile cement-hydrogel composites with largely unaffected application properties. KW - in vitro KW - synergistic reinforcement KW - dihydrate cement KW - porosity KW - mechanical properties KW - dual setting KW - calcium phosphate cements KW - fiber reinforcement KW - polyacrylic acid KW - compressive strength KW - balloon kyphoplasty KW - brushite cement KW - bone cement Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148636 VL - 8 ER - TY - JOUR A1 - Kuenzer, Claudia A1 - Klein, Igor A1 - Ullmann, Tobias A1 - Georgiou, Efi Foufoula A1 - Baumhauer, Roland A1 - Dech, Stefan T1 - Remote Sensing of River Delta Inundation: Exploiting the Potential of Coarse Spatial Resolution, Temporally-Dense MODIS Time Series JF - Remote Sensing N2 - River deltas belong to the most densely settled places on earth. Although they only account for 5% of the global land surface, over 550 million people live in deltas. These preferred livelihood locations, which feature flat terrain, fertile alluvial soils, access to fluvial and marine resources, a rich wetland biodiversity and other advantages are, however, threatened by numerous internal and external processes. Socio-economic development, urbanization, climate change induced sea level rise, as well as flood pulse changes due to upstream water diversion all lead to changes in these highly dynamic systems. A thorough understanding of a river delta's general setting and intra-annual as well as long-term dynamic is therefore crucial for an informed management of natural resources. Here, remote sensing can play a key role in analyzing and monitoring these vast areas at a global scale. The goal of this study is to demonstrate the potential of intra-annual time series analyses at dense temporal, but coarse spatial resolution for inundation characterization in five river deltas located in four different countries. Based on 250 m MODIS reflectance data we analyze inundation dynamics in four densely populated Asian river deltas-namely the Yellow River Delta (China), the Mekong Delta (Vietnam), the Irrawaddy Delta (Myanmar), and the Ganges-Brahmaputra (Bangladesh, India)-as well as one very contrasting delta: the nearly uninhabited polar Mackenzie Delta Region in northwestern Canada for the complete time span of one year (2013). A complex processing chain of water surface derivation on a daily basis allows the generation of intra-annual time series, which indicate inundation duration in each of the deltas. Our analyses depict distinct inundation patterns within each of the deltas, which can be attributed to processes such as overland flooding, irrigation agriculture, aquaculture, or snowmelt and thermokarst processes. Clear differences between mid-latitude, subtropical, and polar deltas are illustrated, and the advantages and limitations of the approach for inundation derivation are discussed. KW - difference water index KW - ENVISAT ASAR WSM KW - TerraSAR-X KW - central asia KW - SAR imagery KW - synthetic aperture radar KW - mekong delta KW - mangrove ecosystems KW - flood detection KW - dynamics Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151552 VL - 7 SP - 8516 EP - 8542 ER - TY - JOUR A1 - Pippias, Maria A1 - Stel, Vianda S. A1 - Diez, José Maria Abad A1 - Afentakis, Nikolaos A1 - Herrero-Calvo, Jose Antonio A1 - Arias, Manuel A1 - Tomilina, Natalia A1 - Caamaño, Encarnación Bouzas A1 - Buturovic-Ponikvar, Jadranka A1 - Čala, Svjetlana A1 - Caskey, Fergus J. A1 - de la Nuez, Pablo Castro A1 - Cernevskis, Harijs A1 - Collart, Frederic A1 - de la Torre, Ramón Alonso A1 - de los Ángeles García Bazaga, Maria A1 - De Meester, Johan A1 - Díaz, Joan Manuel A1 - Djukanovic, Ljubica A1 - Alamar, Manuel Ferrer A1 - Finne, Patrik A1 - Garneata, Liliana A1 - Golan, Eliezer A1 - González Fernández, Raquel A1 - Gutiérrez Avila, Gonzalo A1 - Heaf, James A1 - Hoitsma, Andries A1 - Kantaria, Nino A1 - Kolesnyk, Mykola A1 - Kramar, Reinhard A1 - Kramer, Anneke A1 - Lassalle, Mathilde A1 - Leivestad, Torbjørn A1 - Lopot, Frantisek A1 - Macário, Fernando A1 - Magaz, Angela A1 - Martín-Escobar, Eduardo A1 - Metcalfe, Wendy A1 - Noordzij, Marlies A1 - Palsson, Runolfur A1 - Pechter, Ülle A1 - Prütz, Karl G. A1 - Ratkovic, Marina A1 - Resić, Halima A1 - Rutkowski, Boleslaw A1 - de Pablos, Carmen Santiuste A1 - Spustová, Viera A1 - Süleymanlar, Gültekin A1 - Van Stralen, Karlijn A1 - Thereska, Nestor A1 - Wanner, Christoph A1 - Jager, Kitty J. T1 - Renal replacement therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report JF - Clinical Kidney Journal N2 - Background This article summarizes the 2012 European Renal Association—European Dialysis and Transplant Association Registry Annual Report (available at www.era-edta-reg.org) with a specific focus on older patients (defined as ≥65 years). Methods Data provided by 45 national or regional renal registries in 30 countries in Europe and bordering the Mediterranean Sea were used. Individual patient level data were received from 31 renal registries, whereas 14 renal registries contributed data in an aggregated form. The incidence, prevalence and survival probabilities of patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) and renal transplantation rates for 2012 are presented. Results In 2012, the overall unadjusted incidence rate of patients with ESRD receiving RRT was 109.6 per million population (pmp) (n = 69 035), ranging from 219.9 pmp in Portugal to 24.2 pmp in Montenegro. The proportion of incident patients ≥75 years varied from 15 to 44% between countries. The overall unadjusted prevalence on 31 December 2012 was 716.7 pmp (n = 451 270), ranging from 1670.2 pmp in Portugal to 146.7 pmp in the Ukraine. The proportion of prevalent patients ≥75 years varied from 11 to 32% between countries. The overall renal transplantation rate in 2012 was 28.3 pmp (n = 15 673), with the highest rate seen in the Spanish region of Catalonia. The proportion of patients ≥65 years receiving a transplant ranged from 0 to 35%. Five-year adjusted survival for all RRT patients was 59.7% (95% confidence interval, CI: 59.3–60.0) which fell to 39.3% (95% CI: 38.7–39.9) in patients 65–74 years and 21.3% (95% CI: 20.8–21.9) in patients ≥75 years. KW - end-stage renal disease KW - incidence KW - prevalence KW - renal replacement therapy KW - survival Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150054 VL - 8 IS - 3 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Linker, Ralf A. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Meuth, Sven G. T1 - Report on the 6th scientific meeting of the “Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie” (NEUROWIND e.V.) held in Motzen, Germany, Oct. 31th – Nov. 2nd, 2014 JF - Experimental & Translational Stroke Medicine N2 - From October 31th – November 2nd, 2014, the 6th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. 70 doctoral students and postdocs from over 25 different groups working in German and Swiss university hospitals or research institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. The meeting was regarded as a very well organized platform to support research of young investigators in Germany and all participants enjoyed the stimulating environment for lively in depth discussions. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 4th NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Michael Breckwoldt on his work in the group of Thomas Misgeld (Institute of Neuronal Cell Biology, Technische Universität München, Germany). The successful project was published in Nature Medicine entitled “Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo”. This outstanding paper deals with a molecular imaging approach in living mice to optically analyze the role of mitochondrial redox signals in axons in health and disease. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year’s keynote lecture was given by Bernhard Hemmer, Head of the Department of Neurology at the Klinikum rechts der Isar, Technische Universität München. Dr. Hemmer highlighted the particular role of B cells and (auto)antibodies in multiple sclerosis (MS). As a new highlight Dr. Urbahns, head of global discovery technologies at Merck research laboratories, gave insights from research practice in the pharmaceutical industry and introduced a shift in the view on present-day drug discovery paradigms. Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125049 VL - 7 IS - 1 ER - TY - THES A1 - Wegner, Julia T1 - Restoring tissue-like functionality in circulating CD8 T-cells: mechanistic studies and application in immunomonitoring of cancer patients T1 - Wiederherstellen einer gewebeartigen Funktionalität in humanen CD8 T-Zellen des Blutes: mechanistische Studien und Anwendung beim Immunomonitoring von Krebspatienten N2 - Peripheral blood mononuclear cells (PBMCs) are the only source of human lymphoid cells routinely available for immunologic research and for immunomonitoring of T-cell responses to microbial and tumor-associated antigens. However the large majority of human T-cells resides in tissues, especially in lymphatic organs, while only 1 % of the body’s T-cells circulate in the blood stream. Previous work in mice and humans had indicated that CD4 T-cells transiently lose antigen sensitivity when cellular contacts are lost, e.g. by leaving lymphoid organs such as lymph nodes (LNs) and entering the circulation. In this study, these findings were extended to CD8 T-cells. Thus, CD8 T-cell responses of the human tonsil show a significant drop in sensitivity to viral antigens if tissue-exit was simulated by keeping cells in dispersed culture at body temperature for two hours. Conversely, tissue-like functionality in blood-derived CD8 T-cells was restored by applying the simple and robust RESTORE protocol. Indeed, application of the RESTORE protocol, i.e. pre-culturing PBMCs for two days at a high cell density before initiation of antigenic stimulation, demonstrated that CD8 T-cell responses to a broad range of viral and to tumor-associated antigens are greatly underestimated, and sometimes even remain undetected if conventional, unprocessed PBMC cultures are used. The latter finding is particularly striking with regard to the appearance of Wilms tumor 1 (WT1)-specific CD8 T-cell responses in leukemia patients after allogeneic bone marrow transplantation. My studies on the mechanism of the RESTORE protocol show that HD preculture of PBMCs does not involve antigen-or cytokine-driven clonal expansion of T-cells. Moreover, the gain in antigen sensitivity cannot be explained by a decreased activity of regulatory T-cells during the preculture step. The increased antigen sensitivity of CD8 T-cells from HD precultures of PBMCs is associated with tonic T-cell receptor signaling as indicated by enhanced tyrosine phosphorylation of the CD3 ζ chains and the tyrosine kinase Lck, thereby preparing T-cells for full responses. The upregulation of genes involved in aerobic glycolysis in “restored” CD8 memory T-cells relative to fresh cells might be an essential requirement for increased T-cell functionality including the regulation of IFN-γ production. Taken together, the RESTORE protocol, which was initially described for the CD4 T-cell response to the antibody TGN1412 permits a more meaningful monitoring of CD8 T-cell responses to viral infections and tumors. Furthermore, when generating T-cell lines for adoptive T-cell therapy, the RESTORE protocol allows the generation of CD8 T-cell lines with an improved representation of clones responding to low antigen concentrations. N2 - Mononukleäre Zellen des peripheren Blutes (PBMCs: peripheral blood mononuclear cells) stellen die einzige routinemäßig zugängliche Quelle für humane Lymphozyten dar, welche für die immunologische Forschung und das „Immunomonitoring“ von T-Zellantworten gegen mikrobielle und Tumor-assoziierte Antigene verwendet werden. Jedoch befindet sich der Großteil der T-Zellen des Menschen in Geweben, insbesondere den lymphatischen Organen, wohingegen sich nur 1 % der T-Zellen im Blut aufhalten. Frühere Studien, die sowohl mit murinen als auch mit humanen Zellen durchgeführt wurden, zeigten, dass CD4 T-Zellen ihre Sensitivität gegenüber Antigenen zeitweise verlieren sobald zelluläre Kontakte unterbrochen werden. Dies erfolgt beispielsweise beim Verlassen der T-Zellen von Geweben und dem Eintreten in die Blutzirkulation. In dieser Arbeit wurden diese Beobachtungen auf CD8 T-Zellen ausgeweitet. So weisen humane tonsilläre CD8 T-Zellen eine signifikant niedrigere Sensitivität gegenüber viralen Antigenen auf, wenn diese in Dispersion bei Körpertemperatur für zwei Stunden gehalten werden, um das Verlassen von Geweben und somit den Verlust von zellulären Kontakten zu simulieren. Im Gegenzug konnte eine gewebeähnliche T-Zellfunktionalität bei Blutzellen durch Anwendung des RESTORE Protokolls wiederhergestellt werden. In der Tat zeigte die Anwendung des RESTORE Protokolls, welches eine Vorkultur von PBMCs für zwei Tage bei hoher Zelldichte vor antigenspezifischer T-Zellstimulation einschließt, dass CD8 T-Zellantworten gegen eine Vielzahl viraler und Tumor-assoziierter Antigene deutlich unterschätzt werden, wenn herkömmliche Stimulationsansätze verwendet werden. Teilweise können diese so gemessenen T-Zellantworten bei Verwendung herkömmliche Stimulationsansätze auch gar nicht nachgewiesen werden. Dieser Effekt war bei der Detektion von Wilms Tumor 1 (WT1)-spezifischen CD8 T-Zellantworten bei Leukämiepatienten nach allogener Stammzelltransplantation besonders deutlich zu beobachten. Meine mechanistischen Studien zeigten, dass die Vorkultur von PBMCs bei hoher Zelldichte selbst nicht zu einer Antigen- oder Zytokin-getriebenen T-Zell Expansion führt. Des Weiteren wurde gezeigt, dass der RESTORE Effekt durch den Zugewinn an CD8 T-Zellsensitivität erklärt werden kann und nicht auf eine verringerte CD8 T-Zellsuppression durch regulatorische T-Zellen während der Vorkultur zurückzuführen ist. Die erhöhte Antigensensitivität von vorkultivierten CD8 T-Zellen steht im Zusammenhang mit tonischer T-Zell Signalweiterleitung, welche anhand von erhöhter Tyrosin Phosphorylierung der CD3 ζ Ketten des T-Zell-Rezeptors und der Tyrosinkinase Lck nachgewiesen werden kann. Diese tonischen T-Zellsignale bereiten CD8 T-Zellen darauf vor, bereits auf kleine Mengen Antigen effektiv zu reagieren. Auch die Hochregulierung von Genen, welche der aeroben Glykolyse zuzuordnen sind in vorkultivierten CD8 Gedächtniszellen im Vergleich zu CD8 Gedächtniszellen, welche direkt aus dem Blut isoliert wurden, trägt zu einer erhöhten T-Zellfunktionalität bei, welche die Regulation der IFN-γ Produktion einschließt. Zusammenfassend lässt sich sagen, dass die Anwendung des RESTORE Protokolls, welches ursprünglich zum Nachweis von CD4 T-Zellantworten gegen den Antikörper TGN1412 entwickelt wurde, eine verlässliche Methode zum Nachweis von CD8 T-Zellantworten gegen virale Infektionen und Tumore darstellt. Des Weiteren kann das RESTORE Protokoll zur Generierung von T-Zelllinien in der adoptive T-Zelltherapie eingesetzt werden. Die Anwendung des Protokolls erlaubt das Generieren von Zelllinien, welche auch T-Zellklone beinhalten, die durch Immunantworten auf geringe Antigenkonzentrationen entstanden sind. KW - Antigen CD8 KW - CD8 T cell KW - antigen KW - CD8 T-Zelle KW - RESTORE protocol KW - sensitivity KW - T-Lymphozyt KW - Gewebe Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124177 ER - TY - JOUR A1 - Berenike Herrmann, J. A1 - van Dalen-Oskam, Karina A1 - Schöch, Christof T1 - Revisiting Style, a Key Concept in Literary Studies JF - Journal of Literary Theory N2 - Language and literary studies have studied style for centuries, and even since the advent of ›stylistics‹ as a discipline at the beginning of the twentieth century, definitions of ›style‹ have varied heavily across time, space and fields. Today, with increasingly large collections of literary texts being made available in digital form, computational approaches to literary style are proliferating. New methods from disciplines such as corpus linguistics and computer science are being adopted and adapted in interrelated fields such as computational stylistics and corpus stylistics, and are facilitating new approaches to literary style. The relation between definitions of style in established linguistic or literary stylistics, and definitions of style in computational or corpus stylistics has not, however, been systematically assessed. This contribution aims to respond to the need to redefine style in the light of this new situation and to establish a clearer perception of both the overlap and the boundaries between ›mainstream‹ and ›computational‹ and/or ›empirical‹ literary stylistics. While stylistic studies of non-literary texts are currently flourishing, our contribution deliberately centers on those approaches relevant to ›literary stylistics‹. It concludes by proposing an operational definition of style that we hope can act as a common ground for diverse approaches to literary style, fostering transdisciplinary research. The focus of this contribution is on literary style in linguistics and literary studies (rather than in art history, musicology or fashion), on textual aspects of style (rather than production- or reception-oriented theories of style), and on a descriptive perspective (rather than a prescriptive or didactic one). Even within these limits, however, it appears necessary to build on a broad understanding of the various perspectives on style that have been adopted at different times and in different traditions. For this reason, the contribution first traces the development of the notion of style in three different traditions, those of German, Dutch and French language and literary studies. Despite the numerous links between each other, and between each of them to the British and American traditions, these three traditions each have their proper dynamics, especially with regard to the convergence and/or confrontation between mainstream and computational stylistics. For reasons of space and coherence, the contribution is limited to theoretical developments occurring since 1945. The contribution begins by briefly outlining the range of definitions of style that can be encountered across traditions today: style as revealing a higher-order aesthetic value, as the holistic ›gestalt‹ of single texts, as an expression of the individuality of an author, as an artifact presupposing choice among alternatives, as a deviation from a norm or reference, or as any formal property of a text. The contribution then traces the development of definitions of style in each of the three traditions mentioned, with the aim of giving a concise account of how, in each tradition, definitions of style have evolved over time, with special regard to the way such definitions relate to empirical, quantitative or otherwise computational approaches to style in literary texts. It will become apparent how, in each of the three traditions, foundational texts continue to influence current discussions on literary style, but also how stylistics has continuously reacted to broader developments in cultural and literary theory, and how empirical, quantitative or computational approaches have long ­existed, usually in parallel to or at the margins of mainstream stylistics. The review will also reflect the lines of discussion around style as a property of literary texts – or of any textual entity in general. The perspective on three stylistic traditions is accompanied by a more systematic perspective. The rationale is to work towards a common ground for literary scholars and linguists when talking about (literary) style, across traditions of stylistics, with respect for established definitions of style, but also in light of the digital paradigm. Here, we first show to what extent, at similar or different moments in time, the three traditions have developed comparable positions on style, and which definitions out of the range of possible definitions have been proposed or promoted by which authors in each of the three traditions. On the basis of this synthesis, we then conclude by proposing an operational definition of style that is an attempt to provide a common ground for both mainstream and computational literary stylistics. This definition is discussed in some detail in order to explain not only what is meant by each term in the definition, but also how it relates to computational analyses of style – and how this definition aims to avoid some of the pitfalls that can be perceived in earlier definitions of style. Our definition, we hope, will be put to use by a new generation of computational, quantitative, and empirical studies of style in literary texts. KW - literary studies Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-194349 SN - 1862-8990 SN - 1862-5290 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 9 IS - 1 ER - TY - JOUR A1 - Walz, Yvonne A1 - Wegmann, Martin A1 - Dech, Stefan A1 - Raso, Giovanna A1 - Utzinger, Jürg T1 - Risk profiling of schistosomiasis using remote sensing: approaches, challenges and outlook JF - Parasites & Vectors N2 - Background: Schistosomiasis is a water-based disease that affects an estimated 250 million people, mainly in sub-Saharan Africa. The transmission of schistosomiasis is spatially and temporally restricted to freshwater bodies that contain schistosome cercariae released from specific snails that act as intermediate hosts. Our objective was to assess the contribution of remote sensing applications and to identify remaining challenges in its optimal application for schistosomiasis risk profiling in order to support public health authorities to better target control interventions. Methods: We reviewed the literature (i) to deepen our understanding of the ecology and the epidemiology of schistosomiasis, placing particular emphasis on remote sensing; and (ii) to fill an identified gap, namely interdisciplinary research that bridges different strands of scientific inquiry to enhance spatially explicit risk profiling. As a first step, we reviewed key factors that govern schistosomiasis risk. Secondly, we examined remote sensing data and variables that have been used for risk profiling of schistosomiasis. Thirdly, the linkage between the ecological consequence of environmental conditions and the respective measure of remote sensing data were synthesised. Results: We found that the potential of remote sensing data for spatial risk profiling of schistosomiasis is - in principle - far greater than explored thus far. Importantly though, the application of remote sensing data requires a tailored approach that must be optimised by selecting specific remote sensing variables, considering the appropriate scale of observation and modelling within ecozones. Interestingly, prior studies that linked prevalence of Schistosoma infection to remotely sensed data did not reflect that there is a spatial gap between the parasite and intermediate host snail habitats where disease transmission occurs, and the location (community or school) where prevalence measures are usually derived from. Conclusions: Our findings imply that the potential of remote sensing data for risk profiling of schistosomiasis and other neglected tropical diseases has yet to be fully exploited. KW - ecology KW - scale KW - remote sensing KW - risk profiling KW - spatial modelling KW - schistosomiasis KW - geographical information system KW - intermediate host snail KW - epidemology Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148778 VL - 8 IS - 163 ER - TY - JOUR A1 - Irmer, Henriette A1 - Tarazona, Sonia A1 - Sasse, Christoph A1 - Olbermann, Patrick A1 - Loeffler, Jürgen A1 - Krappmann, Sven A1 - Conesa, Ana A1 - Braus, Gerhard H. T1 - RNAseq analysis of Aspergillus fumigatus in blood reveals a just wait and see resting stage behavior JF - BMC Genomics N2 - Background: Invasive aspergillosis is started after germination of Aspergillus fumigatus conidia that are inhaled by susceptible individuals. Fungal hyphae can grow in the lung through the epithelial tissue and disseminate hematogenously to invade into other organs. Low fungaemia indicates that fungal elements do not reside in the bloodstream for long. Results: We analyzed whether blood represents a hostile environment to which the physiology of A. fumigatus has to adapt. An in vitro model of A. fumigatus infection was established by incubating mycelium in blood. Our model allowed to discern the changes of the gene expression profile of A. fumigatus at various stages of the infection. The majority of described virulence factors that are connected to pulmonary infections appeared not to be activated during the blood phase. Three active processes were identified that presumably help the fungus to survive the blood environment in an advanced phase of the infection: iron homeostasis, secondary metabolism, and the formation of detoxifying enzymes. Conclusions: We propose that A. fumigatus is hardly able to propagate in blood. After an early stage of sensing the environment, virtually all uptake mechanisms and energy-consuming metabolic pathways are shut-down. The fungus appears to adapt by trans-differentiation into a resting mycelial stage. This might reflect the harsh conditions in blood where A. fumigatus cannot take up sufficient nutrients to establish self-defense mechanisms combined with significant growth. KW - Saccharomyces cerevisiae KW - cerebral aspergillosis KW - gene expression KW - Aspergillus fumigatus KW - iron homeostasis KW - invasive pulmonary aspergillosis KW - Candida albicans KW - cell wall KW - lysine biosynthesis KW - human pathogen KW - murine model KW - virulence KW - mRNA-Seq KW - transcriptome KW - human pathogenic fungi KW - secondary metabolite gene cluster KW - detoxification Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151390 VL - 16 IS - 640 ER - TY - THES A1 - Schmitt, Alexandra T1 - Role of Peroxiredoxin 6 in human melanoma T1 - Die Funktion von Peroxiredoxin 6 im humanen Melanom N2 - Peroxiredoxin 6 (PRDX6) is a bifunctional enzyme comprising a peroxidase and a Ca2+-independent phospholipase (iPLA2) activity. This renders the enzyme capable of detoxifying reactive oxygen species (ROS) and of catalyzing the liberation of arachidonic acid (AA) from cellular membranes. Released AA can be further metabolized to bioactive lipids including eicosanoids, which are involved in inflammation, cell growth, differentiation, invasion and proliferation. Human melanoma cells are often characterized by imbalances in both ROS and lipid levels, which can be generated by oncogenic signaling, altered metabolism or UV irradiation. In previous studies, a comparative proteome analysis of the Xiphophorus fish melanoma model revealed a strong upregulation of Prdx6 in benign and malignant lesions compared to healthy skin. As the Xiphophorus melanoma model displays in many respects molecular characteristics that are similar to human melanoma, I investigated the functional role of PRDX6 in human melanoma cells. The first part of the study deals with the regulation of PRDX6 in melanocytes and human melanoma cells. I could demonstrate that the protein level of PRDX6 was strongly enhanced by the induction of the EGFR orthologue Xmrk from the Xiphophorus fish as well as the human EGFR. The upregulation of PRDX6 was further shown to be mediated in a PI3K-dependent and ROS-independent manner. The main part of the thesis comprises the investigation of the functional role of PRDX6 in human melanoma cells as well as the analysis of the underlying mechanism. I could show that knockdown of PRDX6 enhanced the oxidative stress response and led to decreased proliferation of melanoma cells. This cell growth effect was mainly mediated by the iPLA2 activity of PRDX6. Under conditions of strongly enhanced oxidative stress, the peroxidase activity became also important for cellular proliferation. Furthermore, the anti-proliferative effect in cells with lowered PRDX6 levels was the result of reduced cellular AA content and the decrease in the activation of SRC family proteins. Similarly, supplementation with AA led to regeneration of SRC family kinase activity and to an improvement in the reduced proliferation after knockdown of PRDX6. Since AA can be further processed into the prostaglandin PGE2, which has a pro-tumorigenic function in some cancer types, I further examined whether this eicosanoid is involved in the proliferative function of PRDX6. In contrast to AA, PGE2 was not consistently required for melanoma proliferation. In summary, I could demonstrate that PRDX6 plays a major role in AA-dependent lipid signaling in melanoma cells and thereby regulates proliferation. Interestingly, the proliferation relevant iPLA2 activity can be pharmacologically targeted, and melanoma cell growth was clearly blocked by the inhibitor BEL. Thus, I could identify the phospholipase activity of PRDX6 as a new therapeutically interesting target for melanoma treatment. N2 - Peroxiredoxin 6 (PRDX6) ist ein bifunktionales Enzym, welches neben seiner Peroxidase-Aktivität auch eine Ca2+-unabhängige Phospholipase-Aktivität besitzt. Aufgrund dieser beiden Aktivitäten ist das Enzym in der Lage, sowohl oxidativen Stress zu bekämpfen als auch die Freisetzung von Arachidonsäure aus zellulären Membranen zu katalysieren. Freie Arachidonsäure (AA) dient der Generierung von bioaktiven Lipiden wie zum Beispiel Eicosanoiden, welche an Entzündungsreaktionen, Zellwachstum, Differenzierung, Invasion und Proliferation beteiligt sind. Humane Melanomzellen zeichnen sich oft durch ein gestörtes Gleichgewicht reaktiver Sauerstoffspezies und zellulärer Lipide aus. Dieses Ungleichgewicht kann durch onkogene Signalgebung, einen veränderten Metabolismus oder UV-Bestrahlung hervorgerufen werden. Eine vorangegangene Proteomanalyse des Xiphophorus-Fisch-Melanommodells zeigte, dass im Vergleich zur gesunden Haut die Menge an PRDX6 in benignen und malignen Läsionen stark erhöht ist. Da das Xiphophorus-Melanommodell in vielerlei Hinsicht die molekulare Situation des humanen Melanoms wiederspiegelt, habe ich die funktionale Rolle von PRDX6 in humanen Melanomzellen untersucht. Der erste Teil der Studie beschäftigt sich mit der Regulierung von PRDX6 in Melanozyten und humanen Melanomzellen. Ich konnte nachweisen, dass die Menge an PRDX6 Protein durch die Induktion des EGFR Orthologs Xmrk aus Xiphophorus Fischen, sowie des humanen EGFR stark erhöht wurde. Auch konnte ich zeigen, dass die Heraufregulierung von PRDX6 von der Signalgebung der PI3 Kinase, aber nicht von reaktiven Sauerstoffspezies abhängig war. Der Hauptteil der vorliegenden Forschungsarbeit befasst sich mit der Ermittlung der funktionalen Rolle von PRDX6 in humanen Melanomzellen und der Analyse des zugrundeliegenden Mechanismus. Ich konnte nachweisen, dass ein Knockdown von PRDX6 die oxidative Stress-Antwort verstärkte und die Proliferation von Melanomzellen reduzierte. Der Effekt auf das zelluläre Wachstum wurde hierbei hauptsächlich durch die iPLA2-Aktivität von PRDX6 verursacht. Bei stark erhöhtem oxidativem Stress konnte auch eine Relevanz der Peroxidase-Aktivität für die zelluläre Proliferation nachgewiesen werden. Auch ging der anti-proliferative Effekt mit einer Abnahme zellulärer AA und der Reduktion aktiver Kinasen der SRC-Familie einher. Die Zugabe von AA zu Zellen mit PRDX6-Knockdown führte zur Regeneration der SRC-Kinase-Aktivität und konnte die Proliferation wieder verbessern. Da AA zum Prostaglandin PGE2 prozessiert werden kann, welches in einigen Krebsarten pro-tumorigene Funktionen erfüllt, untersuchte ich, ob dieses Eicosanoid auch für die proliferative Funktion von PRDX6 relevant ist. Im Gegensatz zu AA wies PGE2 jedoch keine kontinuierliche pro-proliferative Funktion auf. Zusammenfassend konnte ich zeigen, dass PRDX6 eine entscheidende Rolle im AA- Stoffwechsel von Melanomzellen spielt und hierdurch die Proliferation reguliert. Interessanterweise ist die proliferationsrelevante iPLA2-Aktivität pharmakologisch hemmbar, und auch das Wachstum der Melanomzellen wurde durch den Inhibitor BEL deutlich inhibiert. Mit der Phospholipase-Aktivität von PRDX6 konnte ich somit einen neuen therapeutisch nutzbaren Angriffspunkt für das Melanom identifizieren. KW - Melanom KW - Peroxiredoxin 6 KW - peroxiredoxin 6 KW - Melanom KW - melanoma KW - Arachidonsäure KW - arachidonic acid KW - Prostaglandin E2 KW - prostaglandin E2 KW - Melanomzellen KW - melanoma cells KW - Peroxiredoxin KW - Arachidonsäure KW - Prostaglandin E2 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111465 ER - TY - JOUR A1 - Körner, Anita A1 - Topolinski, Sascha A1 - Strack, Fritz T1 - Routes to Embodiment JF - Frontiers of Psychology N2 - Research on embodiment is rich in impressive demonstrations but somewhat poor in comprehensive explanations. Although some moderators and driving mechanisms have been identified, a comprehensive conceptual account of how bodily states or dynamics influence behavior is still missing. Here, we attempt to integrate current knowledge by describing three basic psychological mechanisms: direct state induction, which influences how humans feel or process information, unmediated by any other cognitive mechanism; modal priming, which changes the accessibility of concepts associated with a bodily state; sensorimotor simulation, which affects the ease with which congruent and incongruent actions are performed. We argue that the joint impact of these mechanisms can account for most existing embodiment effects. Additionally, we summarize empirical tests for distinguishing these mechanisms and suggest a guideline for future research about the mechanisms underlying embodiment effects. KW - priming KW - simulation KW - grounded cognition KW - embodied cognition KW - metaphors Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125960 VL - 9 IS - 940 ER - TY - JOUR A1 - Dandekar, Thomas A1 - Fieselmann, Astrid A1 - Fischer, Eva A1 - Popp, Jasmin A1 - Hensel, Michael A1 - Noster, Janina T1 - Salmonella - how a metabolic generalist adopts an intracellular lifestyle during infection JF - Frontiers in Cellular and Infection Microbiology N2 - The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, "-omics" data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology. KW - enterica serovar Typhimurium KW - bacterial invasion KW - mouse model KW - defenses KW - regulation KW - "-omics" KW - virulence KW - Salmonella-containing vacuole (SCV) KW - metabolism KW - nitric oxide Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149029 VL - 4 IS - 191 ER - TY - JOUR A1 - Gupta, Shishir K. A1 - Kupper, Maria A1 - Ratzka, Carolin A1 - Feldhaar, Heike A1 - Vilcinskas, Andreas A1 - Gross, Roy A1 - Dandekar, Thomas A1 - Förster, Frank T1 - Scrutinizing the immune defence inventory of Camponotus floridanus applying total transcriptome sequencing JF - BMC Genomics N2 - Background Defence mechanisms of organisms are shaped by their lifestyle, environment and pathogen pressure. Carpenter ants are social insects which live in huge colonies comprising genetically closely related individuals in high densities within nests. This lifestyle potentially facilitates the rapid spread of pathogens between individuals. In concert with their innate immune system, social insects may apply external immune defences to manipulate the microbial community among individuals and within nests. Additionally, carpenter ants carry a mutualistic intracellular and obligate endosymbiotic bacterium, possibly maintained and regulated by the innate immune system. Thus, different selective forces could shape internal immune defences of Camponotus floridanus. Results The immune gene repertoire of C. floridanus was investigated by re-evaluating its genome sequence combined with a full transcriptome analysis of immune challenged and control animals using Illumina sequencing. The genome was re-annotated by mapping transcriptome reads and masking repeats. A total of 978 protein sequences were characterised further by annotating functional domains, leading to a change in their original annotation regarding function and domain composition in about 8 % of all proteins. Based on homology analysis with key components of major immune pathways of insects, the C. floridanus immune-related genes were compared to those of Drosophila melanogaster, Apis mellifera, and other hymenoptera. This analysis revealed that overall the immune system of carpenter ants comprises many components found in these insects. In addition, several C. floridanus specific genes of yet unknown functions but which are strongly induced after immune challenge were discovered. In contrast to solitary insects like Drosophila or the hymenopteran Nasonia vitripennis, the number of genes encoding pattern recognition receptors specific for bacterial peptidoglycan (PGN) and a variety of known antimicrobial peptide (AMP) genes is lower in C. floridanus. The comparative analysis of gene expression post immune-challenge in different developmental stages of C. floridanus suggests a stronger induction of immune gene expression in larvae in comparison to adults. Conclusions The comparison of the immune system of C. floridanus with that of other insects revealed the presence of a broad immune repertoire. However, the relatively low number of PGN recognition proteins and AMPs, the identification of Camponotus specific putative immune genes, and stage specific differences in immune gene regulation reflects Camponotus specific evolution including adaptations to its lifestyle. KW - immune system KW - transcriptome KW - carpenter ant KW - camponotus floridanus KW - re-annotation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125279 VL - 16 IS - 540 ER - TY - JOUR T1 - Search for \(W′→t\overline {b}\) in the lepton plus jets final state in proton–proton collisions at a centre-of-mass energy of \(\sqrt {s}\)=8 TeV with the ATLAS detector JF - Physics Letters B N2 - A search for new charged massive gauge bosons, called W′W′, is performed with the ATLAS detector at the LHC, in proton–proton collisions at a centre-of-mass energy of \(\sqrt {s}\)=8 TeV, using a dataset corresponding to an integrated luminosity of 20.3 fb\(^{−1}\). This analysis searches for W′W′ bosons in the \(W′→t\overline{b}\) decay channel in final states with electrons or muons, using a multivariate method based on boosted decision trees. The search covers masses between 0.5 and 3.0 TeV, for right-handed or left-handed W′W′ bosons. No significant deviation from the Standard Model expectation is observed and limits are set on the \(W′→t\overline{b}\) cross-section times branching ratio and on the W′W′-boson effective couplings as a function of the W′W′-boson mass using the CL\(_s\) procedure. For a left-handed (right-handed) W′W′ boson, masses below 1.70 (1.92) TeV are excluded at 95% confidence level. KW - boson Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138262 VL - 743 ER - TY - JOUR T1 - Search for a CP-odd Higgs boson decaying to Zh in pp collisions at \(\sqrt{s}\)=8 TeV with the ATLAS detector JF - Physics Letters B N2 - A search for a heavy, CP-odd Higgs boson, A, decaying into a Z boson and a 125 GeV Higgs boson, h, with the ATLAS detector at the LHC is presented. The search uses proton–proton collision data at a centre-of-mass energy of 8 TeV corresponding to an integrated luminosity of 20.3 fb\(^{-1}\). Decays of CP-even h bosons to ττ or bb pairs with the Z boson decaying to electron or muon pairs are considered, as well as h→bb decays with the Z boson decaying to neutrinos. No evidence for the production of an A boson in these channels is found and the 95% confidence level upper limits derived for σ(gg→A)×BR(A→Zh)×BR(h→f\(\bar{f}\)) are 0.098–0.013 pb for f=τ and 0.57–0.014 pb for f=b in a range of m\(_{A}\)=220–1000 GeVmA=220–1000 GeV. The results are combined and interpreted in the context of two-Higgs-doublet models. KW - BSM Higgs boson KW - ATLAS Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143050 VL - 744 ER - TY - JOUR T1 - Search for a new resonance decaying to a W or Z boson and a Higgs boson in the ℓℓ/ℓν/νν+b\(\overline{b}\) final states with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for a new resonance decaying to a W or Z boson and a Higgs boson in the ℓℓ/ℓν/νν+b\(\overline{b}\) final states is performed using 20.3 fb\(^{−1}\) of pp collision data recorded at \(\sqrt {s}\) = 8 TeV with the ATLAS detector at the Large Hadron Collider. The search is conducted by examining the WH / ZH invariant mass distribution for a localized excess. No significant deviation from the Standard Model background prediction is observed. The results are interpreted in terms of constraints on the Minimal Walking Technicolor model and on a simplified approach based on a phenomenological Lagrangian of Heavy Vector Triplets. KW - Higgs boson KW - W boson KW - Z boson KW - ATLAS detector Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150075 VL - 75 IS - 6 ER - TY - JOUR T1 - Search for dark matter in events with heavy quarks and missing transverse momentum in pp collisions with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - This article reports on a search for dark matter pair production in association with bottom or top quarks in 20.3 fb\(^{−1}\) of pp collisions collected at \(\sqrt {s}\) = 8 TeV by the ATLAS detector at the LHC. Events with large missing transverse momentum are selected when produced in association with high-momentum jets of which one or more are identified as jets containing b-quarks. Final states with top quarks are selected by requiring a high jet multiplicity and in some cases a single lepton. The data are found to be consistent with the Standard Model expectations and limits are set on the mass scale of effective field theories that describe scalar and tensor interactions between dark matter and Standard Model particles. Limits on the dark-matter–nucleon cross-section for spin-independent and spin-dependent interactions are also provided. These limits are particularly strong for low-mass dark matter. Using a simplified model, constraints are set on the mass of dark matter and of a coloured mediator suitable to explain a possible signal of annihilating dark matter. KW - dark matter KW - proton-proton collision KW - ATLAS detector Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150089 VL - 75 IS - 2 ER - TY - JOUR T1 - Search for direct pair production of a chargino and a neutralino decaying to the 125 GeV Higgs boson in \(\sqrt {s}\) = 8 TeV pp collisions with the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search is presented for the direct pair production of a chargino and a neutralino pp → \(\tilde{χ}\)\(^{±}_{1}\)\(\tilde{χ}\)\(^{0}_{2}\), where the chargino decays to the lightest neutralino and the W boson, \(\tilde{χ}\)\(^{±}_{1}\)→\(\tilde{χ}\)\(^{0}_{1}\)(W\(^{±}\)→ℓ\(^{±}\)ν), while the neutralino decays to the lightest neutralino and the 125 GeV Higgs boson, \(\tilde{χ}\)\(^{0}_{2}\)→\(\tilde{χ}\)\(^{0}_{1}\)(h→bb/γγ/ℓ\(^{±}\)νqq). The final states considered for the search have large missing transverse momentum, an isolated electron or muon, and one of the following: either two jets identified as originating from bottom quarks, or two photons, or a second electron or muon with the same electric charge. The analysis is based on 20.3 fb\(^{-1}\) of \(\sqrt {s}\) = 8 TeV proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with the Standard Model expectations, and limits are set in the context of a simplified supersymmetric model. KW - neutralino KW - chargino KW - proton-proton collision KW - Higgs boson KW - ATLAS detector Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150099 VL - 75 IS - 5 ER - TY - JOUR T1 - Search for heavy long-lived multi-charged particles in pp collisions at \(\sqrt {s}\) = 8 TeV using the ATLAS detector JF - European Physical Journal C: Particles and Fields N2 - A search for heavy long-lived multi-charged particles is performed using the ATLAS detector at the LHC. Data collected in 2012 at \(\sqrt {s}\) = 8 TeV from pp collisions corresponding to an integrated luminosity of 20.3 fb\(^{−1}\) are examined. Particles producing anomalously high ionisation, consistent with long-lived massive particles with electric charges from |q| = 2e to |q| = 6e are searched for. No signal candidate events are observed, and 95 % confidence level cross-section upper limits are interpreted as lower mass limits for a Drell–Yan production model. The mass limits range between 660 and 785 GeV. KW - ATLAS detector KW - proton-proton collision Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150100 VL - 75 IS - 8 ER -